Castration induces autoantibody and T cell responses that correlate with inferior outcomes in an androgen‐dependent murine tumor model

• Published in: International journal of cancer 2009-12, Vol.125 (12), p.2871-2878
• Main Authors: Hahn, Sara, Nesslinger, Nancy J., Drapala, Robert J., Bowden, Mary, Rennie, Paul S., Pai, Howard H., Ludgate, Charles, Nelson, Brad H.
• Format: Article
• Language: English
• Subjects: Androgens - pharmacology; Animals; Autoantibodies - immunology; Autoantibodies - metabolism; autoantibody; Biological and medical sciences; Flow Cytometry; hormone therapy; Humans; immune response; Immunoblotting; Immunoenzyme Techniques; Lymphocytes, Tumor-Infiltrating - immunology; Male; Medical sciences; Mice; Neoplasm Recurrence, Local - immunology; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - pathology; Neoplasms, Hormone-Dependent - immunology; Neoplasms, Hormone-Dependent - metabolism; Neoplasms, Hormone-Dependent - pathology; Nephrology. Urinary tract diseases; Orchiectomy; Poly(A)-Binding Protein II - immunology; Poly(A)-Binding Protein II - metabolism; prognosis; prostate cancer; Prostatic Neoplasms - immunology; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; T lymphocyte; T-Lymphocytes - immunology; tumor antigens; tumor recurrence; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Xenograft Model Antitumor Assays
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.24673

We recently reported that hormone therapy induces antigen‐specific autoantibody responses in prostate cancer patients. However, the contribution of autoantibody responses to clinical outcomes is unknown. We used an animal model to test the hypothesis that hormone therapy‐induced immune responses may be associated with delayed tumor recurrence. Male DD/S mice bearing established tumors from the androgen‐dependent Shionogi carcinoma line were castrated to induce tumor regression. Tumor‐specific autoantibody responses were measured by immunoblot, and the underlying antigen was identified by serological screening of a cDNA expression library. T cell responses were assessed by immunohistochemistry and IFN‐γ ELISPOT. Following castration, 97% of mice underwent complete tumor regression. Of these, 72% experienced tumor recurrence 18–79 days postcastration, whereas the remaining 28% remained tumor‐free for the duration of the experiment. In 55% of mice, castration induced autoantibody responses to an antigen identified as poly(A) binding protein nuclear 1 (PABPN1). Castration also induced PABPN1‐specific T cell responses, which were highly correlated to autoantibody responses, and this was accompanied by dense infiltration of tumors by CD3+ T cells 1–2 weeks after castration. Unexpectedly, mice that developed autoantibody and T cell responses to PABPN1 showed a higher rate and shorter latency of tumor recurrence. In mice with recurrent tumors, T cell responses to PABPN1 were still detectable; however, T cell infiltrates were restricted to the peripheral stroma of tumors. In conclusion, castration‐induced immune responses are associated with inferior outcomes in the Shionogi carcinoma model, raising concerns about the influence of treatment‐induced immune responses on clinical outcomes in humans. © 2009 UICC