Impact of androgen-deprivation therapy on the immune system: implications for combination therapy of prostate cancer

Jeanny B. Aragon-Ching¹, Kirsten M. Williams², James L. Gulley³

1Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD,²Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, ³Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD

FIGURES

Figure 1. The Hypothalamic-Pituitary-Gonadal Axis. The hypothalamus/pituitary/testes endocrine loop is shown above. Gonadotropin-releasing hormone (GnRH) stimulates the secretion of gonadotropic hormone (Gn) from the anterior pituitary, and Gn in turn stimulates the production of testosterone. Circulating testosterone acts in a negative feedback loop to down-regulate the expression of GnRH. Adrenocorticotropic hormone (ACTH), also made by the pituitary, stimulates androgen synthesis in the adrenal gland. Testosterone (T) and dihydrotestosterone (DHT) bind to the androgen receptor (AR), causing increased expression of androgen-responsive genes and leading to cell growth.

Figure 2. Overview of Immune System. Bone marrow-derived precursors enter the thymus (T-cell development) and undergo intrathymic development that includes sequential stages of phenotypic maturation, beginning with the DN (double negative) stage. This is followed by expression of CD4 and CD8 DP (double positive) thymocytes and subsequent positive and negative selection events, leading to the generation of MHC class I-restricted cytotoxic CD8+ T cells and MHC class II-restricted helper CD4+ T cells that exit to the periphery as effector T cells in the naïve pool. Memory T cells, as depicted in the memory pool, confer long-term immunity. T_regs characterized by surface expression of CD4+CD25+, some of which are generated from the thymus, are thought to suppress CD4+ and CD8+ T cells by unknown mechanisms. B-cell development in the bone marrow follows differentiation from common lymphocyte precursors (CLP) to the most immature B lineage-committed cells (pro-B) and immunoglobulin heavy chain gene rearrangements in pre-B cell stage. Naïve mature B cells emerge from the marrow bearing the IgM receptor and migrate to secondary lymphoid tissues, where they encounter antigens. Activated B cells secrete IgM and may isotype switch to IgG. Some will further differentiate into plasma cells, secreting antigen-specific IgG antibodies essential for long-term immune response.