[Frontiers in Bioscience E4, 2354-2364, June 1, 2012]
The immune system: endogenous anticancer mechanism
Ana Paula Duarte de Souza1, Cristina Bonorino1
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TABLE OF CONTENTS
1. ABSTRACT
The genetic alterations acquired by cancer cells are identified by diverse immune mechanisms, creating a complex network of interactions that can either favor or control tumor growth. Defects and impairments in the immune system are associated with cancer development. Compelling new evidences are also available regarding the protective value of anti-tumor adaptive immune responses, both local and systemic, developed by the host. More recently, the identification of new subsets of T helper, T cytotoxic, and dendritic cells, unraveled new forms of interactions between immune and tumor cells. The immune system is a powerful ally in the control of cancer development, metastasis and recurrence, due to two important properties that are absent in most anti-cancer treatments - specificity, and long-lasting memory. These properties are being increasingly explored in cancer therapy, from the wide use of monoclonal antibodies to the still experimental dendritic cell based therapies. Now, more than ever, the preservation as well as the recruitment of immune responses in the host constitute important approaches to be applied in cancer therapy.
2. INTRODUCTION
It was long assumed that cancer was a cell-autonomous multistep genetic disease. The genomes of tumor cells in the tumorigenesis process are consistently altered at multiple sites and these genetic alterations drive the progressive transformation of normal cells into malignant derivatives (1). There are six major alterations in cells physiology that collectively dictate malignant growth: (1) Self-sufficiency in growth signals; (2) Insensitivity to growth-inhibitory signals; (3) Evasion of programmed cell death; (4) Limitless replicative potential; (5) Sustained angiogenesis; (6) Tissue invasion and metastasis. Each of these six changes represents the successful breaching of an anticancer defense mechanism hardwired into cells and tissues; consequently these are the six hallmarks of cancer.
The tumor cell microenvironment is made up of stromal and immune cells that can play a significant role in cancer initiation, development, growth, and metastasis (2-4). Immunological pressure, working as an endogenous anticancer mechanism, prevents the outgrowth of malignant cells. Paul Ehrlich in 1909 was the first to propose the concept of immuno surveillance, in which the immune system would scan for nascent transformed cells raising continuously in our bodies and eradicate these transformed cells (5). By 1950's, Burnet and Thomas postulated, based on experimental evidence from tumor transplantation models, that tumors could be repressed by the immune system. Such findings strongly suggested the existence of tumor-associated antigens and formed the basis of the immune surveillance concept (6).
However, in 1970s, immune surveillance was strongly criticized. This hypothesis was formally tested in CBA/H immunodeficient nude mice, which were found to develop spontaneous tumors and chemical carcinogen methylcholantherene (MCA)-induced sarcomas in an equivalent manner to wild-type control mice (7, 8), suggesting that the immune response was not important to tumor control. At that time, these experiments were so convincing that they essentially caused a negation of the cancer immuno surveillance hypothesis. Only now, in retrospection, it is appreciated that there were several caveats associated with these initial experiments. Nude mice that lack a thymus are not entirely immunodeficient, containing NK cells and even low numbers of some functional populations of T cells, which are important to control tumor growth. In addition, the CBA/H strain of mice used in the MCA carcinogenesis experiments expressed a highly active isoform of the enzyme that metabolized MCA to its carcinogenic form. Thus, it was possible that any protective effect of the immune system was covered by the overwhelming efficiency of MCA-induced cellular transformation in the CBA/H strain (9)
Interest in the field of cancer immune surveillance was renewed as a result of studies published approximately 10 years ago, which demonstrated that the immune system can protect against tumor onset and be manipulated to reject established tumors. One important study demonstrated that use of neutralizing antibody to Interferon gamma (IFN-g), an important pro-inflammatory effector cytokine, caused accelerated tumor growth in tumor-bearing mice compared with control, antibody-treated, wild-type mice (10). The finding that IFN-g enhanced tumor cell immunogenicity by up-regulating tumor cell major histocompatibility complex (MHC) class I antigen processing and presentation was particularly important in demonstrating that rejection of these types of tumors was dependent on the development of anti-tumor immunity (11, 12). In addition, mice lacking perforin, an important effector molecule for the cytotoxic function of CD8+ T cells, showed an increased incidence of spontaneous B cell lymphomas compared with wild-type mice (13).
An extensive amount of experimental data from various mouse models of cancer, together with convincing, correlative clinical data from human patients has provided unequivocal evidence that cells of the immune system, innate and adaptive, are required for the prevention of cancer (3). The avoidance of immuno surveillance has thus been proposed to be the seventh hallmark of cancer.
However, tumors can and do arise in the presence of a functional immune system. This could be explained by immunomodulatory properties of cancer and/or tumor recruitment of cells that would hamper immune function within the tumor microenvironment. In addition, it has become evident that both innate and adaptive immunity have a "dark" side and can promote tumor progression. In particular, chronic inflammation, which has long been associated with increased tumor risk, is involved in polarizing immunity towards those effectors that facilitate tumor growth (reviewed in details in (14))
In fact, the dual nature of the immune system to hamper and aid tumor growth has led to the refinement of the cancer immuno surveillance hypothesis into one now termed cancer immunoediting (15-17). During immunoediting, the immune system destroys many pre-cancerous and malignant cells; however, some cells escape the immune response and give rise to progressively growing tumors. Immunoediting is thought to continue throughout the existence of the tumor, so it is very possible that the phenotype of an established tumor has been mainly shaped by the host's immune response.
It was demonstrated by Swann et al that inflammatory-induced cancer and cancer immunoediting can indeed occur in the same mouse tumor model during primary tumorigenesis (18). As a result, the immune system has the potential to either promote or delay tumor onset and progression, and the effectiveness of immune surveillance and the efficacy of immunotherapy depend on the balance between these diametric opposites.
The cancer immunoediting process is envisaged to consist of three phases: elimination, equilibrium, and escape. These have been termed the "three Es of cancer immunoediting". The elimination phase of cancer immunoediting is exactly the same process described in the initial theory of tumor immune surveillance, whereby the immune system detects and eliminates tumor cells that have developed as a result of failed intrinsic tumor suppressor mechanisms. The process of elimination involves innate and adaptive immune responses to tumor cells. The elimination phase can be complete, if all tumor cells are cleared, or incomplete, if only a portion of tumor cells are eliminated, and a temporary state of equilibrium ensues between the immune system and the developing tumor.
During equilibrium tumor cells either remain dormant or continue to evolve, accumulating further changes, such as DNA mutations or changes in gene expression. Such changes can modulate the tumor-specific antigens, and this process leads to the immune selection of tumor cells with reduced immunogenicity, which may occur over a period of many years (9). Chemically induced sarcomas in both nude and severe combined immunodeficiency (SCID) mice were more immunogenic than similar tumors from immunocompetent mice (19, 20). These findings suggest that the original tumor cells induced in normal mice and selected by a T-cell-mediated selection process have been adapted to grow in a host with a functional T-cell system, which has eliminated highly immunogenic tumor cells, leaving low-immunogenic tumor cells to grow. Adaptive immunity plays an important role in occulting cancer cells in an equilibrium state as was demonstrated by Koebel and cols (21).
The pressure exerted by the immune system during the equilibrium phase is sufficient to control tumor progression, but eventually, the process results in the selection of tumor cell variants that are able to resist, avoid, or suppress the antitumor immune response, leading to the escape phase. During the escape phase the immune system is not able to contain tumor growth due to the induction of central or peripheral tolerance. Central tolerance refers to the process by which self-reactive T cells are deleted or converted to a regulatory phenotype in the thymus (22). Clearly, central tolerance fails to eliminate all tumor and/or self reactive T cells, as is evident by the presence of tumor-specific T cells that recognize non-mutated self antigens (23).
When T cells specific for tumor antigens escape central tolerance, tumor growth can induce T cell tolerance in the periphery. One example where tumor growth clearly primes an antitumor immune response that ultimately fails to control tumor growth is that a mouse challenged with a given tumor will reject a subsequent challenge with the same tumor at a distant site, despite the fact that the initial tumor continues to grow (24-26). It has been suggested that T cells from cancer patients have decreased function, due to down regulation of the z chain of the T cell receptor (TCR) and Natural killer (NK) cells receptor (27). However, immunosupression is not a clinical finding commonly associated with cancer. How could that be explained?
Many factors in the tumor microenvironment have been shown to contribute to tumor escape (28). Tumors can express and secrete molecules that lead to immunosupression directly inhibiting the effector cells, or yet recruiting immunosuppressive cells such as regulatory T cells (Tregs) or myeloid derived suppressor cells (MDSCs). Interestingly, tumors may have mechanisms of active tolerization of responses against tumor antigens, sparing responses to other antigens (29). Consequently, it is possible that tumors evolve strategic immunomodulatory mechanisms that affect the anti-tumor response, and yet do not render the host susceptible to infections.
The heterogeneous immune escape strategies and immunomodulatory properties of tumors, as well as the unpredictable responses that tumors present to immunotherapy, suggest that there may be considerable diversity in interactions between tumor and immune cells. Understanding these interactions is of supreme importance to the development of new cancer therapy strategies. The activation of innate and adaptive arms of the immune system by the tumor is dependent on neo-antigens, created by genetic alterations of tumor cells as well as 'danger signals' from damaged or death cells presented in the correct context.
3. THE INNATE ARM - INITIAL RECOGNITION
The initial recognition of tumor cells, or how the unmanipulated immune system can be activated by a developing tumor, has been the object of controversy. Some consider that cellular transformation does not provide sufficient pro-inflammatory signals to activate the immune system in response to a developing tumor, as postulated by the danger hypothesis. The danger hypothesis suggests that the prime role of the immune system is to react to cellular or tissue distress, as opposed simply to non-self (30). Activation of T cells does not occur in the absence of appropriate co-stimulation, which often results in no immune response (anergy) and tolerance (31). More recently some molecules, such as HMGB1 and HSPs, have been proposed to represent endogenous danger signals or damage-associated molecular patterns (DAMPs) from tumors (32, 33). In cancerous conditions, cells dying via non-apoptotic pathways, mainly necrosis, release DAMPs into the extracellular space. These molecules can be released by dying tumor cells and bind to different receptors such as toll like receptors (TLRs), advanced glycosylation end product-specific receptor (RAGE), CD91, LOX1, or CD40, can also stimulate the immune response. DNA-binding molecule high mobility group box 1 (HMGB1) is a DAMP and has been shown to be released from both irradiated and doxorubicin treated tumor cells (34). HMGB1 plays an important role in activation of dendritic cells (DCs) through TLR4 or RAGE (35, 36). However, HMGB1 can also contribute to tumor progression binding TLR4 and TLR2 (37).
Furthermore, it was described that calreticulin exposure in cancer cell death affects tumor immunogenicity (38). Also, necrotic tumor cells can release heat shock proteins (HSPs), such as HSP70, HSP90, and gp96, which stimulate the pattern recognition receptors TLR2 and TLR4. HSPs may facilitate the interaction with surface receptors of antigen-presenting cells (such as CD91, LOX1, CD40) and reportedly mediate the transfer of antigenic peptides from the stressed cell to the antigen-presenting cell (39)
For the innate immune response, several effector cells such as NK, NKT, and (( T cells are activated by inflammatory cytokines, which are released by the growing tumor cells, macrophages and stromal cells surrounding the tumor cells (40). One mechanism by which gamma-delta T cells might control tumor development is through natural killer group 2, member D (NKG2D) recognition of the stress ligand retinoic acid early transcript (RAE1) expressed by tumor cells. Mice lacking gamma-delta T cells are highly susceptible to multiple regimens of cutaneous carcinogenesis (41). In addition, acute upregulation of an NKG2D ligand RAE1 promotes rapid reorganization of a local immune compartment, with the contribution gamma-delta T supporting a initial immuno surveillance (42).
NK cells express both activator and inhibitory receptors that recognize ligands, including cellular stress ligands and MHC class I molecules (43). These receptors provide a balance of signals leading to either activation or inhibition of the NK cell. These recognition receptors allow NK cells to recognize altered malignant cells. Since the seminal discovery that NK cells can eliminate endogenous cells with decreased class I MHC expression (44), a range of NK anti-tumor functions were described. NK and NK T cells mediated killing of the tumor cells by perforin (13), death-inducing molecule (FasL) and TNF-related apoptosis-inducing ligand (TRAIL) (45) releasing tumor antigens, which lead to adaptive immune responses. In addition, NK mediated perforin production is critical for the rejection of tumor cells expressing NKG2D ligands, defining NKG2D as a cytotoxicity inducing receptor (46). NK and NKT cells also produce chemokines that are important for the recruitment of effector T cells, B cells, neutrophils and other NK and NKT cells to the disease site. IL-2- or IL-12-activated NK cells secrete several T cell-recruiting chemokines, including MIP-1-a, MIP-1-b, IL-8, macrophage-derived chemokine, and RANTES (47). NK or NKT-derived IFN-g also upregulates expression of the chemokine receptor CXCR3 that mediates the subsequent recruitment of CXCR3+ T and NK cells to infected tissues (48). The early production of chemokines by NK and NKT cells is likely to have a profound role in shaping the ensuing inflammatory response. In the crosstalk between NK cells and DCs, NK cells promote the maturation of DCs resulting in the enhancement of antigen presentation to naive T cells (49).
Neutrophils are innate immune cells which migrate immediately to sites of tissue damage or inflammation, but some studies have shown that these cells could have anti-tumor effects (50). The recruitment of neutrophils to the tumor site, at their ''N1'' polarization, lead to antitumor activity. Conversely, in the presence of ''N2'' polarized neutrophils, the result is tumor growth. Interestingly, it was demonstrated in models of lung cancer the N1-N2 polarization of tumor infiltrating neutrophils are driven by TGF-b to acquire a polarized N2 protumor phenotype. After TGF-b inhibition, a shift to N1 occurs with acquisition of antitumor activity in vitro and in vivo (51). In study, the neutrophil/lymphocyte ratio in peripheral blood was a good indicator of tumor progression (52), however an excessive production of neutrophils may be unfavorable to anti-cancer immunity (53).
More recently, investigators have focused on the ability of macrophages to infiltrate solid tumors and modulate T-cell and stromal activity to either favor or inhibit tumor growth (54). Whether tumor associated macrophages (TAM) can be converted from the pro-tumorigenic M2 type to the pro-inflammatory M1 type to attack tumors is still under investigation (55, 56). Emerging evidence suggest that in human myeloid leukemias, macrophage phagocytosis is a critical mediator of tumor immunosurveilance. These cancers can escape such immuno surveillance by up-regulating CD47, a potent ''don't eat me'' signal (57).
Immature DCs ingest necrotic tumor cells at the tumor site, acquiring a mature phenotype under appropriated pro-inflammatory conditions and migrating to tumor draining lymph nodes (TDLNs). In the TDLNs, the DCs present tumor antigens to naïve CD4+ and CD8+ specific T cells which expand and differentiate to effectors and memory T cells. Accordingly, DCs play a pivotal role in the initiation, programming, and regulation of tumor-specific immune responses (58, 59). Nevertheless, surprisingly little is known about the role of different DC subsets in cancer initiation and progression in patients.
In mice, there are two main pathways of ontogeny for DC derived from hematopoietic progenitors - see Table 1. One promotes the differentiation of myeloid DC (mDC) also known as conventional DCs (cDC) and the alternate pathway generates plasmacytoid DC (pDC). The cDC subsets in mice can be subdivided into migratory versus lymph node resident cDC. Thus, cDC subsets included the CD11b+ DCs; the CD11b- DCs; and the monocyte-derived inflammatory DCs. Several DCs fall into the CD11b+ DC group, including the CD4+ and CD4-CD8- lymphoid tissue-resident DCs; the classic dermal CD11b+ DCs and their counterparts in the lung and other tissues and the Langerhans cells (CD107+). The CD11b- DC group would include CD8α+ DCs of the lymphoid tissues and the CD103+ langerin+ (CD107+) DCs of the skin, lungs and other tissues. These four groups could be generalized to have broad specializations, with pDCs promoting innate immunity; the CD11b+ DCs stimulating CD4+ T cell help, potentially focused on humoral immunity or responses to extracellular parasites; the CD11b- DCs being dedicated to priming cytotoxic T cell immunity and responses to cell-associated antigens; and the monocyte-derived inflammatory DCs controlling events directly in inflamed tissues, including antigen presentation at effector sites and the initiation of local secondary responses (60).
Most data on subsets of DCs involved in cross-presentation to CD8 T cells, which involves the uptake and processing of exogenous antigens within the major histocompatibility complex (MHC) class I pathway, have been generated in mice (reviewed in (61)). It is generally accepted that migratory DCs (trafficking from the ports of entry or peripheral tissues to LN) carry the antigens (self/tumoral or nonself) to the lymph nodes and operate a transfer to resident CD8a DC that will ensure cross-presentation of the exogenous antigens into MHC class I molecules, the carrier being capable of presenting into MHC class II molecules (62). The DC subset expressing CD8a is particularly effective in cross-presentation to CD8 CTL (61).The CD8a subset of DC appears to originate from the CD8a negative subset by a maturation process involving up regulation of not only CD8a but also the C-type lectin DEC-205 and CD24 (48). The dominant role of this subset in cross-presentation is not due to differences in antigen capture but rather to a greater processing efficiency (63). For instance, a yet unknown preformed molecule that remains associated with necrotic cells (and hence is likely a part of the insoluble cytoskeleton) serves as a ligand for the SYK-coupled C-type lectin receptor Clec9a. Clec9a is expressed on CD8α+ dendritic cells that stimulate the cross-presentation of antigens associated with dead cells (64, 65).
Similarly to mice, humans have two major subsets of DCs, the mDCs and the pDCs. The mDCs comprise different subsets with unique localization, phenotype and functions (review in detail in (66), see also Table 2). In human skin, the epidermis hosts Langerhans cells, whereas the dermis contains CD1a+ DCs and CD14+ DCs. The latter DC subset is involved in the generation of humoral immunity, partly through secretion of interleukin (IL)-12, which stimulates the differentiation of activated B cells into plasma cells and also promotes the differentiation of naïve CD4+ T cells into T follicular helper cells a CD4+ T-cell subset that promotes antibody responses. In contrast, Langerhans cells efficiently prime antigen-specific CD8+ T cells, possibly by means of IL-15. The functions of the predominant CD1a+ dermal DCs are as yet unknown. A particular human DC subset identified by co-expression of CD141 (thrombomodulin, BDCA-3) and the C-type lectin CLEC9A (DNGR-1), is the human counterpart of mouse CD8a+ DCs present in secondary lymphoid organs such as tonsils and spleen and has the ability to cross-present antigens (67, 68)
Cancer is often associated with an environment that does not favour the DC activation events required for proper effector CD4+ and CD8+ T cell activation. DC phenotypes in cancer tissue and draining lymph nodes usually present an ''immature'' phenotype and MDSCs and TAMs adversely affect DC function. Head and neck squamous cell carcinoma diminishes the capacity of pDC to respond to TLR9L for IFN type 1 secretion (69). The prognostic relevance of DC during tumor progression has also been approached in immunohistochemistry analyses, and peritumoral infiltrates of maturing DC in clusters with activated T cells were reported to be associated with a favourable outcome (70).
4. THE ADAPTATIVE ARM - MEMORY DEVELOPMENT
Tumor antigen specific CD4+ and CD8+ T cells primed by DCs in the TDLN home to the primary tumor site, where they exert their effector functions. Cytotoxic CD8+ T cells eliminate the tumor antigen expressing tumor cells and this elimination is enhanced by the secreted IFN-g. IFN-g exerts a limited cytotoxicity via antiproliferative (71) and anti-angiogenic effects (72) and induces apoptosis (73).
During TCR activation in a particular cytokine milieu, naïve CD4 T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, Th17, and iTreg, as defined by their pattern of cytokine production and function. Some studies have also described TGF-b-producing Th3 cells, IL-10-producing TR1 cells, IL-9-producing Th9 cells, and T follicular helper Tfh cells, however cells may not be members of lineages that are distinct from Th1, Th2, Th17, and Treg cells but that rather represent diversity within Th lineages (74). Th1 facilitate tissue destruction and tumor rejection by providing help to CD8 T cells.
Recently identified Th17 cells, produce IL-17, a pro-inflammatory cytokine which plays a dual role in antitumor immunity, since inflammation appears to be a necessity for both metastasis and elimination of tumor cells (75). On the one hand, IL-17 promotes an antitumor cytotoxic T cell response leading to tumor regression. Th17- polarized cells were found to be more effective than Th1 cells in eliminating large established tumors (76). In addition, IL-17 has been shown to inhibit the growth of hematopoietic tumors such as mastocytoma and plasmocytoma by enhancing CTL activity (77). Also, it has been shown that the proliferation and angiogenesis of head neck squamous cell carcinoma are impaired in the presence of Th17 cells (78). On the other hand, IL-17 promotes tumor growth. Apart from a minor direct effect on the proliferation and survival of tumor cells (79), as not all tumor cells express IL-17 receptor and respond to IL-17, the major pro-tumor role of IL-17 in inflammation-associated cancer relies on its pro-angiogenic property of surrounding endothelial cells and fibroblasts (80, 81). Upon activation by IL-23, Th17 cells produce IL-17, which exacerbates inflammation by inducing IL-6, TNF-a, granulocyte colony stimulating factor G-CSF, and other acute phase proteins.
Several studies have revealed that Tregs, which are physiologically engaged in the maintenance of immunological self-tolerance, play critical roles for the control of antitumor immune responses (82). These studies have shown the presence of a large number of Tregs in a variety of tumors and the enhancement of natural as well as vaccine-induced antitumor T-cell responses by systemically or locally removing Tregs (83, 84). In addition to the CD4+CD25+Foxp3+ natural Tregs that develop in the thymus along with other T cells, Tregs can also be induced in the periphery. First, antigenic stimulation of naïve T cells in the presence of Interleukin 10 (IL-10) induces the generation of Type 1 Tregs (Tr1). These Tr1 cells do not express Foxp3 but produce IL-10 and TGF-b as their major immune suppressive mechanism (85). Second, antigenic stimulation of naïve T cells in the presence of transforming growth factor-b (TGF-b) induces the generation of T helper 3 (Th3) cells in vivo and in vitro (86), which subsequently produce TGF-b as their major immune suppressive mechanism. In addition to IL-10 and TGF-b, it has also been shown that IL-4 and IL-13 can induce the generation of Foxp3+ Tregs from naïve CD4 T cells in a process that is independent of IL-10 or TGF-b (87). The discovery that the early differentiation of Treg and Th17 cells from naive CD4+ T cells shares a requirement for TGF-b indicated that there is substantial plasticity in the early and late stages of Th17 and Treg cell development (88).
T cell immunity to several tumor antigens, such as Human epidermal growth factor receprto 2 (HER-2/neu), carcino-embryonic antigen (CEA), Cell surface associated mucin 1 (MUC1) and NY-ESO-1, has been reported (89, 90). However, the tumor remains not totally controlled by the immune system, one of the reasons being that, unlike pathogens, they do not express potent rejection antigens. Tumor vaccination aims at stimulating a systemic immune response targeted to mostly weak antigens expressed in the disseminated tumor lesions. Paramount challenges in developing effective vaccination protocols are the identification of potent and broadly expressed tumor rejection antigens. Interesting, some tumor types exhibit a particular type of genetic instability referred to as microsatellite instability (MSI), where defects in DNA mismatch repair mechanisms lead to the duplication or deletion of short repeated sequences of DNA known as microsatellites. The high rate of mutation in MSI-H tumors has been shown to result in the generation of a number of novel tumor antigens that can be recognized by infiltrating B cells (91), CD4+ T cells (92), and CD8+ T cells (91) and this infiltration is associated with a favorable prognostic. An alternative approach in which the expression of new, and thereby potent, antigens are induced in tumor cells by inhibiting nonsense-mediated messenger RNA decay was proposed by Fernando Pastor and colleages (93). Small interfering RNA (siRNA)-mediated inhibition of nonsense-mediated messenger RNA decay in tumor cells led to the expression of new antigenic determinants and their immune-mediated rejection.
Although several studies have shown that naïve CD8+ T cells can become activated in the TDLN during tumor outgrowth, whether naïve CD8+ T cells are activated in the tumor mass itself remains to be established. Recently, Thompson and colleagues have shown, in a murine model, that naive tumor-specific CD8+ T cells can infiltrate the tumor, and be activated in situ, acquire an effector phenotype and proliferate in response to a specific antigen. To directly show that OT-I T cells were activated in the tumor and not in the draining lymph nodes, lymph node development was inhibited in mice in utero (94)
B cell antibodies (Ab) responses were thought to contribute modestly, if at all, to tumor immunity (95), whereas Ab production may contribute to chronic inflammation that enhances tumor development (96, 97). However, in a recent study it was demonstrated that B cells are required for optimal CD4 and CD8 T cells tumor immunity. They show that depletion of B cell enhances B16 melanoma growth (98)
An important attribute of the adaptive immune system is the ability to remember a prior encounter with an antigen; an ability termed immunological memory. Bigger, better, and stronger responses are mounted upon a secondary encounter with the antigen potentially resulting in clearance before the development of disease (99) Sallusto and Lanzavecchia introduced the concept that memory T cells are heterogeneous (100). Central memory T cells circulate between secondary lymphoid organs, express the LN homing molecules CCR7 and CD62L, and do not exhibit immediate effector functions but can undergo significant recall proliferation upon antigen re-encounter. Effector memory T cells classically lack LN homing molecules and are thus generally deposited in and circulate through peripheral tissues. They exhibit immediate effector function upon antigen recognition.
High infiltrates of memory T cells (CD3/CD45RO) or (CD8/CD45RO) in center of the tumor and invasive margins were highly and significantly associated with very good prognosis, both in terms of disease-free and overall survival (101). Tumors with low memory T or memory-cytotoxic T cells in both zones were associated with very bad clinical outcome. The fact that it is not only the overall quantity or even the functional orientation, but also the location of the immune cells that influences tumor recurrence supports the concept that distinct cells with selective functions located in different tumor regions may play a crucial role in controlling metastasis escape.
5. IMMUNOTHERAPY - FROM EXPERIMENTAL TO COMMERCIAL
Today, a diagnosis of cancer is not necessarily a death sentence: there were nearly 9 million cancer "survivors" living in the United States in 1999 (102) suggesting that current cancer treatments are effective. However, the standard options - surgery, radiotherapy, and chemotherapy - have debilitating and distressing side effects, destroying healthy tissues along with cancer cells. Currently, basic and clinical research is centered on developing so called therapeutic cancer vaccines for patients who already have cancer. Cancer vaccines consisting of antigens of varied composition, identity, and source have been studied clinically. Products might consist of antigens that are recombinant proteins, synthetic peptides, carbohydrates, extracted tumor-derived proteins, or monoclonal antibodies. Alternatively, the product might be DNA encoding the antigen of interest. The identity of the antigen used depends on the type of cancer, although some antigens are associated with multiple types. For example, CEA is the target for several colorectal cancer vaccines, whereas MUC-1 and HER-2 are target antigens for several breast cancer vaccines.
Whole cells displaying cancer-associated antigens can also be used as vaccines. Cells can be derived from two sources: the cancer itself and the immune system. In the first instance, cancer cells are killed (usually by irradiation), then modified either genetically or chemically to increase their immunogenic potential. The identity of the tumor-specific antigens need not be known because the cell itself becomes the vaccine and the immunological key to the destruction of its cancerous relatives. The second method involves producing DCs that directly present the tumor antigen to the immune system. The DCs are loaded with the desired antigen using electroporation and can also be genetically modified to secrete an additional immune response stimulant such as granulocyte macrophage colony stimulating factor (GM-CSF). Sipuleucel-T is a novel immunotherapeutic consisting of autologous dendritic cells which have been pulsed ex vivo with PA2024 as a source of antigen. PA2024 is a recombinant fusion protein consisting of granulocyte-macrophage colony-stimulating factor (GM-CSF) and prostatic acid phosphatase. With the FDA approval of Sipuleucel-T for prostate cancer, active immunization has become an accepted approach for the treatment of established cancer (103).
Also, a wide array of cell based immunotherapies utilizing T cells and NK cells, have been established. One example is the adoptive cell transfer of tumor-infiltrating lymphocytes in combination with lymphodepletion that has proven to be an effective treatment for metastatic melanoma patients, with an objective response rate in 50%-70% of the patients (104) .
In addition to the strategies indicated above, the inhibition of immunosuppressive mechanisms associated with tumor infiltration by the immune system using RNA interference also offers a new approach to vaccine design. For instance, TLR agonists have been shown to boost immune responses toward tumors. Furthermore, a rapidly expanding repertoire of monoclonal antibodies is being developed to treat tumors, and many of the available antibodies have demonstrated impressive clinical responses. One good example is ipilimumab that blocks cytotoxic T lymphocyte antigen 4 (CTLA-4), a key negative regulator of T cell activity and potentiates antitumor responses (105).
Immunotherapy will likely not be able to eliminate tumors by itself, but combination therapies that incorporate immunotherapeutic agents have great potential for providing clinical success in treating cancer in the coming years (106).
6. REFERENCES
1. Hanahan, D. & R. A. Weinberg: The hallmarks of cancer. Cell, 100, 57-70 (2000)
http://dx.doi.org/10.1016/S0092-8674(00)81683-9
2. Weinberg, R. A.: Coevolution in the tumor microenvironment. Nat Genet, 40, 494-5 (2008)
http://dx.doi.org/10.1038/ng0508-494
PMid:18443582
3. Swann, J. B. & M. J. Smyth: Immune surveillance of tumors. J Clin Invest, 117, 1137-46 (2007)
http://dx.doi.org/10.1172/JCI31405
PMid:17476343 PMCid:1857231
4. Spiotto, M. T., D. A. Rowley & H. Schreiber: Bystander elimination of antigen loss variants in established tumors. Nat Med, 10, 294-8 (2004)
http://dx.doi.org/10.1038/nm999
PMid:14981514
5. Ehrlich, P.: Ueber den jetzigen stand der karzinomoforschung. Ned Tijdschr Geneeskd, 5, 73-290 (1909)
6. Burnet, M.: Cancer; a biological approach. I. The processes of control. Br Med J, 1, 779-86 (1957)
http://dx.doi.org/10.1136/bmj.1.5022.779
PMid:13404306 PMCid:1973174
7. Stutman, O.: Tumor development after 3-methylcholanthrene in immunologically deficient athymic-nude mice. Science, 183, 534-6 (1974)
http://dx.doi.org/10.1126/science.183.4124.534
PMid:4588620
8. Stutman, O.: Immunodepression and malignancy. Adv Cancer Res, 22, 261-422 (1975)
http://dx.doi.org/10.1016/S0065-230X(08)60179-7
9. Teng, M. W., J. B. Swann, C. M. Koebel, R. D. Schreiber & M. J. Smyth: Immune-mediated dormancy: an equilibrium with cancer. J Leukoc Biol, 84, 988-93 (2008)
http://dx.doi.org/10.1189/jlb.1107774
PMid:18515327
10. Dighe, A. S., E. Richards, L. J. Old & R. D. Schreiber: Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFN gamma receptors. Immunity, 1, 447-56 (1994)
http://dx.doi.org/10.1016/1074-7613(94)90087-6
11. Kaplan, D. H., V. Shankaran, A. S. Dighe, E. Stockert, M. Aguet, L. J. Old & R. D. Schreiber: Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci U S A, 95, 7556-61 (1998)
http://dx.doi.org/10.1073/pnas.95.13.7556
12. Shankaran, V., H. Ikeda, A. T. Bruce, J. M. White, P. E. Swanson, L. J. Old & R. D. Schreiber: IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature, 410, 1107-11 (2001)
http://dx.doi.org/10.1038/35074122
PMid:11323675
13. Smyth, M. J., K. Y. Thia, S. E. Street, D. MacGregor, D. I. Godfrey & J. A. Trapani: Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J Exp Med, 192, 755-60 (2000)
http://dx.doi.org/10.1084/jem.192.5.755
PMid:10974040 PMCid:2193269
14. Grivennikov, S. I., F. R. Greten & M. Karin: Immunity, inflammation, and cancer. Cell, 140, 883-99 (2010)
http://dx.doi.org/10.1016/j.cell.2010.01.025
PMid:20303878 PMCid:2866629
15. Dunn, G. P., A. T. Bruce, H. Ikeda, L. J. Old & R. D. Schreiber: Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol, 3, 991-8 (2002)
http://dx.doi.org/10.1038/ni1102-991
PMid:12407406
16. Dunn, G. P., L. J. Old & R. D. Schreiber: The immunobiology of cancer immunosurveillance and immunoediting. Immunity, 21, 137-48 (2004)
http://dx.doi.org/10.1016/j.immuni.2004.07.017
PMid:15308095
17. Dunn, G. P., L. J. Old & R. D. Schreiber: The three Es of cancer immunoediting. Annu Rev Immunol, 22, 329-60 (2004)
http://dx.doi.org/10.1146/annurev.immunol.22.012703.104803
PMid:15032581
18. Swann, J. B., M. D. Vesely, A. Silva, J. Sharkey, S. Akira, R. D. Schreiber & M. J. Smyth: Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis. Proc Natl Acad Sci U S A, 105, 652-6 (2008)
http://dx.doi.org/10.1073/pnas.0708594105
PMid:18178624 PMCid:2206591
19. Engel, A. M., I. M. Svane, J. Rygaard & O. Werdelin: MCA sarcomas induced in scid mice are more immunogenic than MCA sarcomas induced in congenic, immunocompetent mice. Scand J Immunol, 45, 463-70 (1997)
http://dx.doi.org/10.1046/j.1365-3083.1997.d01-419.x
PMid:9160088
20. Svane, I. M., A. M. Engel, M. B. Nielsen, H. G. Ljunggren, J. Rygaard & O. Werdelin: Chemically induced sarcomas from nude mice are more immunogenic than similar sarcomas from congenic normal mice. Eur J Immunol, 26, 1844-50 (1996)
http://dx.doi.org/10.1002/eji.1830260827
PMid:8765030
21. Koebel, C. M., W. Vermi, J. B. Swann, N. Zerafa, S. J. Rodig, L. J. Old, M. J. Smyth & R. D. Schreiber: Adaptive immunity maintains occult cancer in an equilibrium state. Nature, 450, 903-7 (2007)
http://dx.doi.org/10.1038/nature06309
PMid:18026089
22. Kyewski, B. & L. Klein: A central role for central tolerance. Annu Rev Immunol, 24, 571-606 (2006)
http://dx.doi.org/10.1146/annurev.immunol.23.021704.115601
PMid:16551260
23. Scanlan, M. J., A. J. Simpson & L. J. Old: The cancer/testis genes: review, standardization, and commentary. Cancer Immun, 4, 1 (2004)
PMid:14738373
24. Kurt, R. A., J. A. Park, M. C. Panelli, S. F. Schluter, J. J. Marchalonis, B. Carolus & E. T. Akporiaye: T lymphocytes infiltrating sites of tumor rejection and progression display identical V beta usage but different cytotoxic activities. J Immunol, 154, 3969-74 (1995)
PMid:7706735
25. Kurt, R. A., J. A. Park, S. F. Schluter, J. J. Marchalonis & E. T. Akporiaye: TCR v (beta) usage and clonality of T cells isolated from progressing and rejected tumor sites before and after in vitro culture. Int Immunol, 12, 639-46 (2000)
http://dx.doi.org/10.1093/intimm/12.5.639
PMid:10784610
26. Blohm, U., E. Roth, K. Brommer, T. Dumrese, F. M. Rosenthal & H. Pircher: Lack of effector cell function and altered tetramer binding of tumor-infiltrating lymphocytes. J Immunol, 169, 5522-30 (2002)
PMid:12421928
27. Mizoguchi, H., J. J. O'Shea, D. L. Longo, C. M. Loeffler, D. W. McVicar & A. C. Ochoa: Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science, 258, 1795-8 (1992)
http://dx.doi.org/10.1126/science.1465616
PMid:1465616
28. de Souza, A. P. & C. Bonorino: Tumor immunosuppressive environment: effects on tumor-specific and nontumor antigen immune responses. Expert Rev Anticancer Ther, 9, 1317-32 (2009)
http://dx.doi.org/10.1586/era.09.88
PMid:19761435
29. de Souza, A. P., T. de Jesus Borges, M. M. Pillat & C. Bonorino: CD4 (+) T cell response against a non-tumor antigen is unaffected in melanoma-bearing mice. Cancer Immunol Immunother, Jan;60(1):145-51 (2011)
30. Matzinger, P.: Tolerance, danger, and the extended family. Annu Rev Immunol, 12, 991-1045 (1994)
http://dx.doi.org/10.1146/annurev.iy.12.040194.005015
PMid:8011301
31. Schwartz, R. H.: T cell anergy. Annu Rev Immunol, 21, 305-34 (2003)
http://dx.doi.org/10.1146/annurev.immunol.21.120601.141110
PMid:12471050
32. van der Most, R. G., A. J. Currie, B. W. Robinson & R. A. Lake: Decoding dangerous death: how cytotoxic chemotherapy invokes inflammation, immunity or nothing at all. Cell Death Differ, 15, 13-20 (2008)
http://dx.doi.org/10.1038/sj.cdd.4402255
PMid:18007666
33. Tesniere, A., T. Panaretakis, O. Kepp, L. Apetoh, F. Ghiringhelli, L. Zitvogel & G. Kroemer: Molecular characteristics of immunogenic cancer cell death. Cell Death Differ, 15, 3-12 (2008)
http://dx.doi.org/10.1038/sj.cdd.4402269
PMid:18007663
34. Sims, G. P., D. C. Rowe, S. T. Rietdijk, R. Herbst & A. J. Coyle: HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol, 28, 367-88 (2010)
http://dx.doi.org/10.1146/annurev.immunol.021908.132603
PMid:20192808
35. Dumitriu, I. E., P. Baruah, B. Valentinis, R. E. Voll, M. Herrmann, P. P. Nawroth, B. Arnold, M. E. Bianchi, A. A. Manfredi & P. Rovere-Querini: Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products. J Immunol, 174, 7506-15 (2005)
PMid:15944249
36. Apetoh, L., F. Ghiringhelli, A. Tesniere, M. Obeid, C. Ortiz, A. Criollo, G. Mignot, M. C. Maiuri, E. Ullrich, P. Saulnier, H. Yang, S. Amigorena, B. Ryffel, F. J. Barrat, P. Saftig, F. Levi, R. Lidereau, C. Nogues, J. P. Mira, A. Chompret, V. Joulin, F. Clavel-Chapelon, J. Bourhis, F. Andre, S. Delaloge, T. Tursz, G. Kroemer & L. Zitvogel: Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med, 13, 1050-9 (2007)
http://dx.doi.org/10.1038/nm1622
PMid:17704786
37. Ellerman, J. E., C. K. Brown, M. de Vera, H. J. Zeh, T. Billiar, A. Rubartelli & M. T. Lotze: Masquerader: high mobility group box-1 and cancer. Clin Cancer Res, 13, 2836-48 (2007)
http://dx.doi.org/10.1158/1078-0432.CCR-06-1953
PMid:17504981
38. Obeid, M., A. Tesniere, F. Ghiringhelli, G. M. Fimia, L. Apetoh, J. L. Perfettini, M. Castedo, G. Mignot, T. Panaretakis, N. Casares, D. Metivier, N. Larochette, P. van Endert, F. Ciccosanti, M. Piacentini, L. Zitvogel & G. Kroemer: Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med, 13, 54-61 (2007)
http://dx.doi.org/10.1038/nm1523
PMid:17187072
39. Henderson, B., S. K. Calderwood, A. R. Coates, I. Cohen, W. van Eden, T. Lehner & A. G. Pockley: Caught with their PAMPs down? The extracellular signalling actions of molecular chaperones are not due to microbial contaminants. Cell Stress Chaperones, 15, 123-41 (2010)
http://dx.doi.org/10.1007/s12192-009-0137-6
PMid:19731087 PMCid:2866984
40. Street, S. E., Y. Hayakawa, Y. Zhan, A. M. Lew, D. MacGregor, A. M. Jamieson, A. Diefenbach, H. Yagita, D. I. Godfrey & M. J. Smyth: Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and gammadelta T cells. J Exp Med, 199, 879-84 (2004)
http://dx.doi.org/10.1084/jem.20031981
PMid:15007091 PMCid:2212720
41. Girardi, M., D. E. Oppenheim, C. R. Steele, J. M. Lewis, E. Glusac, R. Filler, P. Hobby, B. Sutton, R. E. Tigelaar & A. C. Hayday: Regulation of cutaneous malignancy by gammadelta T cells. Science, 294, 605-9 (2001)
http://dx.doi.org/10.1126/science.1063916
PMid:11567106
42. Strid, J., S. J. Roberts, R. B. Filler, J. M. Lewis, B. Y. Kwong, W. Schpero, D. H. Kaplan, A. C. Hayday & M. Girardi: Acute upregulation of an NKG2D ligand promotes rapid reorganization of a local immune compartment with pleiotropic effects on carcinogenesis. Nat Immunol, 9, 146-54 (2008)
http://dx.doi.org/10.1038/ni1556
PMid:18176566
43. Lanier, L. L.: NK cell recognition. Annu Rev Immunol, 23, 225-74 (2005)
http://dx.doi.org/10.1146/annurev.immunol.23.021704.115526
PMid:15771571
44. Karre, K., H. G. Ljunggren, G. Piontek & R. Kiessling: Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature, 319, 675-8 (1986)
http://dx.doi.org/10.1038/319675a0
PMid:3951539
45. Mori, S., A. Jewett, K. Murakami-Mori, M. Cavalcanti & B. Bonavida: The participation of the Fas-mediated cytotoxic pathway by natural killer cells is tumor-cell-dependent. Cancer Immunol Immunother, 44, 282-90 (1997)
http://dx.doi.org/10.1007/s002620050384
PMid:9247563
46. Hayakawa, Y., J. M. Kelly, J. A. Westwood, P. K. Darcy, A. Diefenbach, D. Raulet & M. J. Smyth: Cutting edge: tumor rejection mediated by NKG2D receptor-ligand interaction is dependent upon perforin. J Immunol, 169, 5377-81 (2002)
PMid:12421908
47. Sawaki, J., H. Tsutsui, N. Hayashi, K. Yasuda, S. Akira, T. Tanizawa & K. Nakanishi: Type 1 cytokine/chemokine production by mouse NK cells following activation of their TLR/MyD88-mediated pathways. Int Immunol, 19, 311-20 (2007)
http://dx.doi.org/10.1093/intimm/dxl148
PMid:17289654
48. Martin-Fontecha, A., L. L. Thomsen, S. Brett, C. Gerard, M. Lipp, A. Lanzavecchia & F. Sallusto: Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T (H)1 priming. Nat Immunol, 5, 1260-5 (2004)
http://dx.doi.org/10.1038/ni1138
PMid:15531883
49. Zitvogel, L., M. Terme, C. Borg & G. Trinchieri: Dendritic cell-NK cell cross-talk: regulation and physiopathology. Curr Top Microbiol Immunol, 298, 157-74 (2006)
http://dx.doi.org/10.1007/3-540-27743-9_8
50. Stoppacciaro, A., C. Melani, M. Parenza, A. Mastracchio, C. Bassi, C. Baroni, G. Parmiani & M. P. Colombo: Regression of an established tumor genetically modified to release granulocyte colony-stimulating factor requires granulocyte-T cell cooperation and T cell-produced interferon gamma. J Exp Med, 178, 151-61 (1993)
http://dx.doi.org/10.1084/jem.178.1.151
PMid:7686211
51. Fridlender, Z. G., J. Sun, S. Kim, V. Kapoor, G. Cheng, L. Ling, G. S. Worthen & S. M. Albelda: Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. Cancer Cell, 16, 183-94 (2009)
http://dx.doi.org/10.1016/j.ccr.2009.06.017
PMid:19732719 PMCid:2754404
52. Liu, H., Tabuchi, T., Takemura, A., Kasuga, T., Motohashi, G., Hiraishi, K., Katano, M, Nakada, I, Ubukata, H., Tabuchi, T.: The granulocyte/lymphocyte ratio as an independent predictor of tumour growth, metastasis and progression: Its clinical applications. Molecular Medicine Reports, 1, 699-702 (2008)
PMid:21479473
53. Liu, H., H. Ubukata, T. Tabuchi, A. Takemura, G. Motohashi, M. Nishimura, T. Satani, J. Hong, M. Katano, I. Nakada, A. R. Saniabadi & T. Tabuchi: It is possible that tumour-infiltrating granulocytes promote tumour progression. Oncol Rep, 22, 29-33 (2009)
http://dx.doi.org/10.3892/or_00000402
PMCid:2829240
54. Klimp, A. H., E. G. de Vries, G. L. Scherphof & T. Daemen: A potential role of macrophage activation in the treatment of cancer. Crit Rev Oncol Hematol, 44, 143-61 (2002)
http://dx.doi.org/10.1016/S1040-8428(01)00203-7
55. Mantovani, A., P. Allavena, S. Sozzani, A. Vecchi, M. Locati & A. Sica: Chemokines in the recruitment and shaping of the leukocyte infiltrate of tumors. Semin Cancer Biol, 14, 155-60 (2004)
http://dx.doi.org/10.1016/j.semcancer.2003.10.001
PMid:15246050
56. Sica, A., P. Larghi, A. Mancino, L. Rubino, C. Porta, M. G. Totaro, M. Rimoldi, S. K. Biswas, P. Allavena & A. Mantovani: Macrophage polarization in tumour progression. Semin Cancer Biol, 18, 349-55 (2008)
http://dx.doi.org/10.1016/j.semcancer.2008.03.004
PMid:18467122
57. Jaiswal, S., M. P. Chao, R. Majeti & I. L. Weissman: Macrophages as mediators of tumor immunosurveillance. Trends Immunol, 31, 212-9 (2010)
http://dx.doi.org/10.1016/j.it.2010.04.001
PMid:20452821
58. Steinman, R. M. & J. Banchereau: Taking dendritic cells into medicine. Nature, 449, 419-26 (2007)
http://dx.doi.org/10.1038/nature06175
PMid:17898760
59. Dhodapkar, M. V., K. M. Dhodapkar & A. K. Palucka: Interactions of tumor cells with dendritic cells: balancing immunity and tolerance. Cell Death Differ, 15, 39-50 (2008)
http://dx.doi.org/10.1038/sj.cdd.4402247
PMid:17948027 PMCid:2762352
60. Heath, W. R. & F. R. Carbone: Dendritic cell subsets in primary and secondary T cell responses at body surfaces. Nat Immunol, 10, 1237-44 (2009)
http://dx.doi.org/10.1038/ni.1822
PMid:19915624
61. Heath, W. R., G. T. Belz, G. M. Behrens, C. M. Smith, S. P. Forehan, I. A. Parish, G. M. Davey, N. S. Wilson, F. R. Carbone & J. A. Villadangos: Cross-presentation, dendritic cell subsets, and the generation of immunity to cellular antigens. Immunol Rev, 199, 9-26 (2004)
http://dx.doi.org/10.1111/j.0105-2896.2004.00142.x
PMid:15233723
62. Villadangos, J. A. & P. Schnorrer: Intrinsic and cooperative antigen-presenting functions of dendritic-cell subsets in vivo. Nat Rev Immunol, 7, 543-55 (2007)
http://dx.doi.org/10.1038/nri2103
PMid:17589544
63. Schnorrer, P., G. M. Behrens, N. S. Wilson, J. L. Pooley, C. M. Smith, D. El-Sukkari, G. Davey, F. Kupresanin, M. Li, E. Maraskovsky, G. T. Belz, F. R. Carbone, K. Shortman, W. R. Heath & J. A. Villadangos: The dominant role of CD8+ dendritic cells in cross-presentation is not dictated by antigen capture. Proc Natl Acad Sci U S A, 103, 10729-34 (2006)
http://dx.doi.org/10.1073/pnas.0601956103
PMid:16807294 PMCid:1502299
64. Sancho, D., O. P. Joffre, A. M. Keller, N. C. Rogers, D. Martinez, P. Hernanz-Falcon, I. Rosewell & C. Reis e Sousa: Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature, 458, 899-903 (2009)
http://dx.doi.org/10.1038/nature07750
PMid:19219027 PMCid:2671489
65. Sancho, D., D. Mourao-Sa, O. P. Joffre, O. Schulz, N. C. Rogers, D. J. Pennington, J. R. Carlyle & C. Reis e Sousa: Tumor therapy in mice via antigen targeting to a novel, DC-restricted C-type lectin. J Clin Invest, 118, 2098-110 (2008)
http://dx.doi.org/10.1172/JCI34584
PMid:18497879 PMCid:2391066
66. Ueno, H., N. Schmitt, E. Klechevsky, A. Pedroza-Gonzalez, T. Matsui, G. Zurawski, S. Oh, J. Fay, V. Pascual, J. Banchereau & K. Palucka: Harnessing human dendritic cell subsets for medicine. Immunol Rev, 234, 199-212 (2010)
http://dx.doi.org/10.1111/j.0105-2896.2009.00884.x
PMid:20193020 PMCid:2847489
67. Poulin, L. F., M. Salio, E. Griessinger, F. Anjos-Afonso, L. Craciun, J. L. Chen, A. M. Keller, O. Joffre, S. Zelenay, E. Nye, A. Le Moine, F. Faure, V. Donckier, D. Sancho, V. Cerundolo, D. Bonnet & C. Reis e Sousa: Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8alpha+ dendritic cells. J Exp Med, 207, 1261-71 (2010)
http://dx.doi.org/10.1084/jem.20092618
PMid:20479117 PMCid:2882845
68. Jongbloed, S. L., A. J. Kassianos, K. J. McDonald, G. J. Clark, X. Ju, C. E. Angel, C. J. Chen, P. R. Dunbar, R. B. Wadley, V. Jeet, A. J. Vulink, D. N. Hart & K. J. Radford: Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J Exp Med, 207, 1247-60 (2010)
http://dx.doi.org/10.1084/jem.20092140
PMid:20479116 PMCid:2882828
69. Hartmann, E., B. Wollenberg, S. Rothenfusser, M. Wagner, D. Wellisch, B. Mack, T. Giese, O. Gires, S. Endres & G. Hartmann: Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer. Cancer Res, 63, 6478-87 (2003)
PMid:14559840
70. Ladanyi, A., J. Kiss, B. Somlai, K. Gilde, Z. Fejos, A. Mohos, I. Gaudi & J. Timar: Density of DC-LAMP (+) mature dendritic cells in combination with activated T lymphocytes infiltrating primary cutaneous melanoma is a strong independent prognostic factor. Cancer Immunol Immunother, 56, 1459-69 (2007)
http://dx.doi.org/10.1007/s00262-007-0286-3
PMid:17279413
71. Gollob, J. A., C. J. Sciambi, Z. Huang & H. K. Dressman: Gene expression changes and signaling events associated with the direct antimelanoma effect of IFN-gamma. Cancer Res, 65, 8869-77 (2005)
http://dx.doi.org/10.1158/0008-5472.CAN-05-1387
PMid:16204058
72. Qin, Z., J. Schwartzkopff, F. Pradera, T. Kammertoens, B. Seliger, H. Pircher & T. Blankenstein: A critical requirement of interferon gamma-mediated angiostasis for tumor rejection by CD8+ T cells. Cancer Res, 63, 4095-100 (2003)
PMid:12874012
73. Wall, L., F. Burke, C. Barton, J. Smyth & F. Balkwill: IFN-gamma induces apoptosis in ovarian cancer cells in vivo and in vitro. Clin Cancer Res, 9, 2487-96 (2003)
PMid:12855622
74. Zhu, J., H. Yamane & W. E. Paul: Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol, 28, 445-89 (2010)
http://dx.doi.org/10.1146/annurev-immunol-030409-101212
PMid:20192806
75. Murugaiyan, G. & B. Saha: Protumor vs antitumor functions of IL-17. J Immunol, 183, 4169-75 (2009)
http://dx.doi.org/10.4049/jimmunol.0901017
PMid:19767566
76. Muranski, P., A. Boni, P. A. Antony, L. Cassard, K. R. Irvine, A. Kaiser, C. M. Paulos, D. C. Palmer, C. E. Touloukian, K. Ptak, L. Gattinoni, C. Wrzesinski, C. S. Hinrichs, K. W. Kerstann, L. Feigenbaum, C. C. Chan & N. P. Restifo: Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood, 112, 362-73 (2008)
http://dx.doi.org/10.1182/blood-2007-11-120998
PMid:18354038 PMCid:2442746
77. Benchetrit, F., A. Ciree, V. Vives, G. Warnier, A. Gey, C. Sautes-Fridman, F. Fossiez, N. Haicheur, W. H. Fridman & E. Tartour: Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism. Blood, 99, 2114-21 (2002)
http://dx.doi.org/10.1182/blood.V99.6.2114
PMid:11877287
78. Kesselring, R., A. Thiel, R. Pries, T. Trenkle & B. Wollenberg: Human Th17 cells can be induced through head and neck cancer and have a functional impact on HNSCC development. Br J Cancer, 103, 1245-54 (2010)
http://dx.doi.org/10.1038/sj.bjc.6605891
PMid:20877351
79. Zhang, B., G. Rong, H. Wei, M. Zhang, J. Bi, L. Ma, X. Xue, G. Wei, X. Liu & G. Fang: The prevalence of Th17 cells in patients with gastric cancer. Biochem Biophys Res Commun, 374, 533-7 (2008)
http://dx.doi.org/10.1016/j.bbrc.2008.07.060
PMid:18655770
80. Numasaki, M., M. Watanabe, T. Suzuki, H. Takahashi, A. Nakamura, F. McAllister, T. Hishinuma, J. Goto, M. T. Lotze, J. K. Kolls & H. Sasaki: IL-17 enhances the net angiogenic activity and in vivo growth of human non-small cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis. J Immunol, 175, 6177-89 (2005)
PMid:16237115
81. Tartour, E., F. Fossiez, I. Joyeux, A. Galinha, A. Gey, E. Claret, X. Sastre-Garau, J. Couturier, V. Mosseri, V. Vives, J. Banchereau, W. H. Fridman, J. Wijdenes, S. Lebecque & C. Sautes-Fridman: Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. Cancer Res, 59, 3698-704 (1999)
PMid:10446984
82. Nishikawa, H. & S. Sakaguchi: Regulatory T cells in tumor immunity. Int J Cancer, 127, 759-67 (2010)
PMid:20518016
83. Onizuka, S., I. Tawara, J. Shimizu, S. Sakaguchi, T. Fujita & E. Nakayama: Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res, 59, 3128-33 (1999)
PMid:10397255
84. Sutmuller, R. P., L. M. van Duivenvoorde, A. van Elsas, T. N. Schumacher, M. E. Wildenberg, J. P. Allison, R. E. Toes, R. Offringa & C. J. Melief: Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25 (+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med, 194, 823-32 (2001)
http://dx.doi.org/10.1084/jem.194.6.823
PMid:11560997 PMCid:2195955
85. Groux, H., A. O'Garra, M. Bigler, M. Rouleau, S. Antonenko, J. E. de Vries & M. G. Roncarolo: A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature, 389, 737-42 (1997)
http://dx.doi.org/10.1038/39614
PMid:9338786
86. Chen, W., W. Jin, N. Hardegen, K. J. Lei, L. Li, N. Marinos, G. McGrady & S. M. Wahl: Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med, 198, 1875-86 (2003)
http://dx.doi.org/10.1084/jem.20030152
PMid:14676299 PMCid:2194145
87. Skapenko, A., J. R. Kalden, P. E. Lipsky & H. Schulze-Koops: The IL-4 receptor alpha-chain-binding cytokines, IL-4 and IL-13, induce forkhead box P3-expressing CD25+CD4+ regulatory T cells from CD25-CD4+ precursors. J Immunol, 175, 6107-16 (2005)
PMid:16237107
88. Bettelli, E., Y. Carrier, W. Gao, T. Korn, T. B. Strom, M. Oukka, H. L. Weiner & V. K. Kuchroo: Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature, 441, 235-8 (2006)
http://dx.doi.org/10.1038/nature04753
PMid:16648838
89. Rentzsch, C., S. Kayser, S. Stumm, I. Watermann, S. Walter, S. Stevanovic, D. Wallwiener & B. Guckel: Evaluation of pre-existent immunity in patients with primary breast cancer: molecular and cellular assays to quantify antigen-specific T lymphocytes in peripheral blood mononuclear cells. Clin Cancer Res, 9, 4376-86 (2003)
PMid:14555509
90. Disis, M. L., K. L. Knutson, K. Schiffman, K. Rinn & D. G. McNeel: Pre-existent immunity to the HER-2/neu oncogenic protein in patients with HER-2/neu overexpressing breast and ovarian cancer. Breast Cancer Res Treat, 62, 245-52 (2000)
http://dx.doi.org/10.1023/A:1006438507898
PMid:11072789
91. Ishikawa, T., T. Fujita, Y. Suzuki, S. Okabe, Y. Yuasa, T. Iwai & Y. Kawakami: Tumor-specific immunological recognition of frameshift-mutated peptides in colon cancer with microsatellite instability. Cancer Res, 63, 5564-72 (2003)
PMid:14500396
92. Saeterdal, I., J. Bjorheim, K. Lislerud, M. K. Gjertsen, I. K. Bukholm, O. C. Olsen, J. M. Nesland, J. A. Eriksen, M. Moller, A. Lindblom & G. Gaudernack: Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer. Proc Natl Acad Sci U S A, 98, 13255-60 (2001)
http://dx.doi.org/10.1073/pnas.231326898
PMid:11687624 PMCid:60857
93. Pastor, F., D. Kolonias, P. H. Giangrande & E. Gilboa: Induction of tumour immunity by targeted inhibition of nonsense-mediated mRNA decay. Nature, 465, 227-30 (2010)
http://dx.doi.org/10.1038/nature08999
PMid:20463739 PMCid:3107067
94. Thompson, E. D., H. L. Enriquez, Y. X. Fu & V. H. Engelhard: Tumor masses support naive T cell infiltration, activation, and differentiation into effectors. J Exp Med, 207, 1791-804 (2010)
http://dx.doi.org/10.1084/jem.20092454
PMid:20660615 PMCid:2916130
95. Manson, L. A.: Anti-tumor immune responses of the tumor-bearing host: the case for antibody-mediated immunologic enhancement. Clin Immunol Immunopathol, 72, 1-8 (1994)
http://dx.doi.org/10.1006/clin.1994.1099
PMid:8020182
96. Houghton, A. N., H. Uchi & J. D. Wolchok: The role of the immune system in early epithelial carcinogenesis: B-ware the double-edged sword. Cancer Cell, 7, 403-5 (2005)
http://dx.doi.org/10.1016/j.ccr.2005.04.026
PMid:15894259
97. de Visser, K. E., L. V. Korets & L. M. Coussens: De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell, 7, 411-23 (2005)
http://dx.doi.org/10.1016/j.ccr.2005.04.014
PMid:15894262
98. DiLillo, D. J., K. Yanaba & T. F. Tedder: B cells are required for optimal CD4+ and CD8+ T cell tumor immunity: therapeutic B cell depletion enhances B16 melanoma growth in mice. J Immunol, 184, 4006-16 (2010)
http://dx.doi.org/10.4049/jimmunol.0903009
PMid:20194720
99. Wakim, L. M. & M. J. Bevan: From the thymus to longevity in the periphery. Curr Opin Immunol, 22, 274-8 (2010)
http://dx.doi.org/10.1016/j.coi.2010.03.003
PMid:20378321 PMCid:2904522
100. Sallusto, F., D. Lenig, R. Forster, M. Lipp & A. Lanzavecchia: Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature, 401, 708-12 (1999)
http://dx.doi.org/10.1038/44385
PMid:10537110
101. Galon, J., A. Costes, F. Sanchez-Cabo, A. Kirilovsky, B. Mlecnik, C. Lagorce-Pages, M. Tosolini, M. Camus, A. Berger, P. Wind, F. Zinzindohoue, P. Bruneval, P. H. Cugnenc, Z. Trajanoski, W. H. Fridman & F. Pages: Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science, 313, 1960-4 (2006)
http://dx.doi.org/10.1126/science.1129139
PMid:17008531
102. Edwards, B. K., H. L. Howe, L. A. Ries, M. J. Thun, H. M. Rosenberg, R. Yancik, P. A. Wingo, A. Jemal & E. G. Feigal: Annual report to the nation on the status of cancer, 1973-1999, featuring implications of age and aging on U.S. cancer burden. Cancer, 94, 2766-92 (2002)
http://dx.doi.org/10.1002/cncr.10593
PMid:12173348
103. O'Neill, D. W.: Dendritic cells and T cells in immunotherapy. J Drugs Dermatol, 9, 1383-92 (2010)
PMid:21061761
104. Hershkovitz, L., J. Schachter, A. J. Treves & M. J. Besser: Focus on adoptive T cell transfer trials in melanoma. Clin Dev Immunol, 2010, 260267 (2010)
http://dx.doi.org/10.1155/2010/260267
PMid:21234353 PMCid:3018069
105. Hoos, A., R. Ibrahim, A. Korman, K. Abdallah, D. Berman, V. Shahabi, K. Chin, R. Canetta & R. Humphrey: Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy. Semin Oncol, 37, 533-46 (2010)
http://dx.doi.org/10.1053/j.seminoncol.2010.09.015
PMid:21074069
106. Borghaei, H., M. R. Smith & K. S. Campbell: Immunotherapy of cancer. Eur J Pharmacol, 625, 41-54 (2009)
http://dx.doi.org/10.1016/j.ejphar.2009.09.067
PMid:19837059 PMCid:2783916
Abbreviations: MCA methylcholantherene, IL Interleukin, TGFb Transforming Growth Factor, IFN-g Interferon gamma, MHC I Major histocompatibility complex, MDSCs Myeloid derived suppressor cells, DAMPs Damage-associated molecular patterns, TLRs Toll like receptors, RAGE Glycosylation and product specific receptor, HMGB1 DNA-binding molecule high mobility group 1, DCs dendritic cells, HSP heat shock proteins, RAE retinoic acid early transcript, NKG2D natural killer group 2, TRAIL TNF related apoptosis inducing ligand, TAM tumor associated macrophages, TDLN tumor draining lymph node, Th T helper, CEA carcino embryonic antigen, GMCSF granulocyte macrophage colony stimulating factor, MUC1 Cell surface associated mucin 1, HER2neu Human epidermal growth factor receptor 2, MSI microsatellite instability, siRNA small interfering RNA, CTLA 4 cytotoxic T cell lymphocyte antigen 4
Key Words: Cancer, Immune system, Tumor immunoediting, Immunessupression, Review
Send correspondence to: Cristina Bonorino, Departamento de Biologia Celular e Molecular, FABIO, Instituto de Pesquisas Biomedicas, PUCRS, Av. Ipiranga, 6690 2o andar, 90610-000 Porto Alegre, RS, Brazil, Tel: 55 51 33203545, Fax: 55 51 33203312, E-mail:cbonorino@pucrs.com