Partially circumventing peripheral tolerance for oncogene-specific prostate cancer immunotherapy.
BACKGROUND
Failure of cancer immunotherapy is essentially due to immunological tolerance to tumor-associated antigens (TAAs), as these antigens are also expressed in healthy tissues.


METHODS
Here, we used transgenic adenocarcinoma of mouse prostate (TRAMP) mice, which develop lethal prostate cancer due to prostate-specific expression of SV40 T antigen (Tag), to evaluate effects of prostatic transformation on oncogene TAA-specific tolerance and to test the possibility of breaking such tolerance using a modified recombinant vaccinia virus.


RESULTS
We showed that Tag expression in TRAMP mice is uniquely extra-thymic, and levels of prostatic Tag expression positively correlate with malignant transformation of the prostate. Yet, young tumor-free TRAMP mice were tolerant to Tag antigen. We therefore attempted overcoming such peripheral oncogene-specific T cell tolerance through immunization with a vaccinia construct encoding Tag immunogenic epitopes. This vaccination modality showed that oncogene-specific tolerance was successfully overcome by effective in vivo priming of Tag-specific cytotoxic T cells (CTLs). However, this was restricted to young TRAMP mice. Tag-specific CTL from "tumor naïve" young TRAMP mice showed significant anti-tumor efficacy in vivo by eliminating established heterotopic prostate tumors and prolonging survival in SCID mice harboring Tag-expressing tumors. In contrast, older TRAMP mice with established prostate tumors exhibited oncogene-specific tolerance as evidenced by failure to generate Tag-specific CTL following Tag-specific immunization.


CONCLUSIONS
Peripheral tolerance can be overcome for effective anti-tumor therapy following oncogene-specific immunization. However, this ability to elicit oncogene-specific CTL is impeded in the tumor-bearing host, in the context of increased oncogene expression associated with tumor progression.
Neeley
Yilin C
YC
Department of Urology, Surgery, and Pathology, University of Michigan. Ann Arbor, Michigan, USA.
Arredouani
Mohamed S
MS
Hollenbeck
Brent
B
Eng
Marvin H
MH
Rubin
Mark A
MA
Sanda
Martin G
MG
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000276:immunology*; D000970:Antineoplastic Agents / Q000276:immunology*; D015139:Blotting, Southern; D015153:Blotting, Western; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D007108:Immune Tolerance; D007124:Immunoenzyme Techniques; D016219:Immunotherapy, Adoptive; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014616:Vaccinia virus / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D000952:Antigens, Polyomavirus Transforming; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D011994:Recombinant Proteins