Castration induces autoantibody and T cell responses that correlate with inferior outcomes in an androgen-dependent murine tumor model.
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-gamma 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.
Hahn
Sara
S
Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
Nesslinger
Nancy J
NJ
Drapala
Robert J
RJ
Bowden
Mary
M
Rennie
Paul S
PS
Pai
Howard H
HH
Ludgate
Charles
C
Nelson
Brad H
BH
D000728:Androgens / Q000494:pharmacology; D000818:Animals; D001323:Autoantibodies / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009376:Neoplasms, Hormone-Dependent / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009919:Orchiectomy; D039103:Poly(A)-Binding Protein II / Q000276:immunology* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D000728:Androgens; D001323:Autoantibodies; D039103:Poly(A)-Binding Protein II