Standard Treatments Induce Antigen-Specific Immune Responses in Prostate Cancer

Abstract

Purpose: Prostate tumors express antigens that are recognized by the immune system in a significant proportion of patients; however, little is known about the effect of standard treatments on tumor-specific immunity. Radiation therapy induces expression of inflammatory and immunestimulatory molecules, and neoadjuvant hormone therapy causes prominent T-cell infiltration of prostate tumors. We therefore hypothesized that radiation therapy and hormone therapy may initiate tumor-specific immune responses. Experimental Design: Pretreatment and posttreatment serum samples from 73 men with nonmetastatic prostate cancer and 50 cancer-free controls were evaluated by Western blotting and SEREX (serological identification of antigens by recombinant cDNA expression cloning) antigen arrays to examine whether autoantibody responses to tumor proteins arose during the course of standard treatment. Results: Western blotting revealed the development of treatment-associated autoantibody responses in patients undergoing neoadjuvant hormone therapy (7 of 24, 29.2%), external beam radiation therapy (4 of 29, 13.8%), and brachytherapy (5 of 20, 25%), compared with 0 of 14 patients undergoing radical prostatectomy and 2 of 36 (5.6%) controls. Responses were seen within 4 to 9 months of initiation of treatment and were equally prevalent across different disease risk groups. Similarly, in the murine Shionogi tumor model, hormone therapy induced tumorassociated autoantibody responses in 5 of 10 animals. In four patients, SEREX immunoscreening of a prostate cancer cDNA expression library identified several antigens recognized by treatmentassociated autoantibodies, including PARP1, ZNF707 + PTMA, CEP78, SDCCAG1, and ODF2. Conclusion: We show for the first time that standard treatments induce antigen-specific immune responses in prostate cancer patients. Thus, immunologic mechanisms may contribute to clinical outcomes after hormone and radiation therapy, an effect that could potentially be exploited as a practical, personalized form of immunotherapy.

Resistance of CD45RA− T Cells to Apoptosis and Functional Impairment, and Activation of Tumor-Antigen Specific T Cells during Radiation Therapy of Prostate Cancer

“…Ab responses against autoantigens were identified by SEREX in nonmetastatic PCa patients undergoing standard RT or brachytherapy (34). New autoantibody responses were observed in 14% of patients after RT and in 20% of patients after brachytherapy.…”

The anticancer immune response: indispensable for therapeutic success?

“…Androgen ablation in prostate cancer patients may activate immune responses to some prostate tumor antigens by increasing the pool of naive T cells (as demonstrated by TCR rearrangement excision circle [TREC] analyses; TRECs are stable DNA circles excised from T cell germline DNA to allow for TCR formation during early T cell development and exist in high concentrations in thymic emigrants), decreasing and/or diluting the population of Tregs, and favoring the concomitant infiltration of T cells into tumor beds (36,37). One study performed on 73 men bearing nonmetastatic prostate cancer and 50 controls showed that neoadjuvant hormonal and radiation therapy (but not radical prostatectomy) can elicit a tumor-specific autoantibody response (38). Humoral responses arose early and were durable in most cases, prompting the manipulation of B cell responses by immunotherapy.…”

CD20+ B Cells: The Other Tumor-Infiltrating Lymphocytes

“…A wide variety of tumor Ags are recognized, including overexpressed proteins (e.g., HER-2/neu), aberrantly expressed proteins (e.g., cancertestis Ags), and a plethora of apparently normal self-proteins (41,42). Furthermore, standard treatments for cancer, such as hormone and radiation therapy, can trigger additional autoantibody responses, presumably through presentation of dying tumor cells to the immune system (43).…”