Immunology and immunotherapy approaches for prostate cancer

Abstract

Several mechanisms that impair the immune response to promote tumour progression are reported. These mechanisms aim to reduce the ability of antigen-presenting cells to present antigen and activate naïve T cells to support an active immune response or to create a suppressive environment that induce non-functional tumour-associated antigen-specific T cells. Prostate cancer (PC) alone accounts for 33% of incident cancer cases and about 9% of all cancer-related deaths among men in the USA during 2006. Whereas androgen deprivation has remained the first line of therapy for advanced PC, other therapies are still required due to progression to an androgen-resistant state and eventually loss of control in patients receiving hormonal therapy. Immunotherapy seems to be a promising approach to enhance tumour-specific T-cell responses in different cancers including prostate. More importantly, clinical trials in advanced PC patients have shown that immunotherapy may generate significant clinical responses. Immunology and immunotherapy aspects of PC with focus on prostate-specific antigen will be presented.

Cell-Intrinsic Abrogation of TGF-β Signaling Delays but Does Not Prevent Dysfunction of Self/Tumor-Specific CD8 T Cells in a Murine Model of Autochthonous Prostate Cancer

“…Additionally, identifying and targeting tumor-specific antigens not expressed by normal cells may circumvent or delay functional exhaustion by reducing the extent of persistent antigen stimulation. However, while some unique tumor-specific epitopes have been discovered in select tumors, tumor-specific antigens are often unique to each patient and the majority of antigens being targeted in clinical trials, including all known targetable prostate cancer antigens, are self-antigens (24, 78–80). …”

“…In large part this reflects identification of immunogenic prostate-restricted antigens that are expressed in malignant and normal prostate tissues but not other tissues that might be potential targets of toxicity, and that can elicit cytolytic T cell responses (24). However, TGFβ is present and necessary for normal prostate homeostasis, and is found in increased levels in the malignant prostate (25, 26), which can pose a substantive obstacle to T cell therapy of this tumor.…”

SPAS-1 (stimulator of prostatic adenocarcinoma-specific T cells)/SH3GLB2: A prostate tumor antigen identified by CTLA-4 blockade

“…It is only through the recent development of more effective vaccination strategies that some of the preexisting immune tolerance to these self-antigens was overcome. As a result, promising biological outcomes are emerging in clinical trials (6,7). We believe, however, that the efficacy of prostate cancer immunotherapies could be further improved if target antigens were identified through a functional approach rather than selected a priori based upon tissue expression.…”

Combination Immunotherapy with 4-1BBL and CTLA-4 Blockade for the Treatment of Prostate Cancer

“…The prostate cancer vaccine alone was unable to cause complete tumor regression, which could reflect either that the initial CD8 + T-cell-mediated antitumor immune response simply is not potent enough to completely eliminate all the cancer cells or that the cancer cells have lost their immunogenicity. There might be several reasons for that including (1) low-level expression of the major MHC molecules, (2) absence of recognized tumor Ags, (3) poor costimulatory molecule expression, or (4) some kind of immunosuppression of the CD8 + T-cell response such as TGF- β [18]. 4-1BB is an inducible member of the TNFR superfamily that has profound effects on T cells, including activation of both CD4 + and CD8 + T cells, enhanced expansion [19, 20], increased long-term survival [21, 22], and antiapoptosis of activation-induced CD8 + T cells [23].…”