[Frontiers in Bioscience 10, 1396-1414 May 1, 2005]

ADENOVIRUS E1A GENE-INDUCED TUMOR REJECTION THROUGH CELLULAR SENSITIZATION TO IMMUNE AND NONIMMUNE APOPTOTIC INJURIES

James L. Cook 1 and John M. Routes 2

1 Section of Infectious Diseases, Depts of Medicine, Microbiology and Immunology and the Cancer Center, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, 2 Depts of Medicine and Immunology, National Jewish Medical and Research Center and University of Colorado Health Sciences Center (UCHSC) and the UCHSC Cancer Center, Denver, CO 80206

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Review
3.1 Association between E1A oncogene expression in neoplastic cells and their reduced tumorigenicity in the context of the cell-mediated immune response of the host
3.1.1. Maturation of the cellular immune response related to Ad-transformed cell rejection
3.1.2. The role of innate immunity in the rejection of E1A-expressing tumor cells
3.2. The concept of E1A-induced cytolytic susceptibility related to E1A-induced changes in the tumorigenic phenotype of neoplastic cells
3.2.1. DNA virus tumor antigens and cytolytic susceptibility
3.2.2. E1A oncogene-induced cytolytic susceptibility to innate immune-effector cells
3.2.3. E1A oncogene-induced reduction of tumorigenicity
3.2.4 .E1A oncoprotein effects on adaptive (E1A-specific) cellular immune defenses
3.2.5. Integrated model of the synergistic antitumor effect of innate and adaptive immunity
3.3. Cytolytic mechanisms to which E1A sensitizes tumor cells
3.3.1. E1A-induced sensitization of target cells to both degranulation-dependent and degranulation-independent killing by cytolytic lymphocytes at a "post-recognition" stage in the interaction
3.3.2. E1A oncoprotein expression-level-dependence of cytolytic susceptibility
3.3.3. Role of E1A-induced cellular sensitivity to TNF family ligands in cytolytic susceptibility
3.3.4. Blockade of immune-mediated killing of E1A-positive cells by expression of the other Ad early genes
3.3.5. E1A induced cellular sensitization to both immune-mediated and nonimmune-induced apoptotic injuries
3.3.6. "Direct" induction of apoptosis by E1A during viral infection or attempted cellular immortalization
3.3.7. "Indirect" sensitization of E1A-expressing cells to apoptotic injuries
3.4. Molecular mechanisms through which E1A mediates the conversion of cells from the cytolytic resistant to the cytolytic susceptible phenotype
3.4.1. Lack of a correlation between E1A induced cytolytic susceptibility and modulation of MHC class I antigen control of NK cell cytolytic activity
3.4.2. Definition of post-recognition mechanisms of induction of cytolytic susceptibility and sensitization to apoptotic injury - E1A Gene mapping studies
3.4.3. Definition of molecular mechanisms of E1A-induced cytolytic susceptibility and sensitization to apoptotic injury - Apoptosis pathway studies
3.4.3.1. p53 family members
3.4.3.2. Bcl-2 family members
3.4.3.3 .E1A-induced repression of the NF-kappa B-dependent cellular defense against apoptosis
3.5. Translation of observations regarding E1A-induced cytolytic susceptibility and sensitization to apoptotic injury to studies of human tumor cells and in vivo assays of tumorigenicity
4. Perspective
5. Acknowledgments
6. References

1. ABSTRACT

The E1A gene of human adenovirus (Ad) serotypes 2 and 5 induces susceptibility of cells from several species, including human, to lysis by natural killer cells, activated macrophages and a variety of other immunologic and nonimmune cellular injuries. This E1A activity is the rationale behind some treatment strategies using combined adenoviral vector infection and chemotherapy for cancer. This review will consider the evolution of the studies that have resulted in the current understanding of the cellular mechanisms of E1A-induced tumor cell cytolytic susceptibility and sensitization to apoptotic injury. The translation of in vitro observations to experimental models testing E1A-induced tumor rejection in the context of the cellular immune response and E1A-induced sensitization of human tumor cells to therapeutic injuries will be discussed. Review of available information on the molecular mechanisms of E1A-induced cellular sensitivity to immune and nonimmune injuries will be used as a basis for consideration of possible future directions of this research.