Peripheral T-cell tolerance associated with prostate cancer is independent from CD4+CD25+ regulatory T cells.
CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) are thought to suppress the natural and vaccine-induced immune response against tumor-associated antigens (TAA). Here, we show that Treg accumulate in tumors and tumor-draining lymph nodes of aging transgenic adenocarcinoma of the mouse prostate (TRAMP) male mice, which spontaneously develop prostate cancer. TAA overexpression and disease progression associate also with induction of TAA-specific tolerance. TAA-specific T cells were found in the lymphoid organs of tumor-bearing mice. However, they had lost the ability to release IFN-gamma and kill relevant targets. Neither in vivo depletion of Treg by PC61 monoclonal antibody followed by repeated vaccinations with antigen-pulsed dendritic cells nor the combined treatment with 1-methyl-L-tryptophan inhibitor of the enzyme indoleamine 2,3-dyoxigenase, PC61 antibody, and dendritic cell vaccination restored the TAA-specific immune response. Treg did not seem to control the early phases of tolerance induction, as well. Indeed, depletion of Treg, starting at week 6, the age at which TRAMP mice are not yet tolerant, and prolonged up to week 12, did not avoid tolerance induction. A similar accumulation of Treg was found in the lymph nodes draining the site of dendritic cell vaccination both in TRAMP and wild-type animals. Hence, we conclude that Treg accrual is a phenomenon common to the sites of an ongoing immune response, and in TRAMP mice in particular, Treg are dispensable for induction of tumor-specific tolerance.
Degl'Innocenti
Elena
E
Cancer Immunotherapy and Gene Therapy Program, Istituto Scientifico San Raffaele, Milan, Italy.
Grioni
Matteo
M
Capuano
Giusy
G
Jachetti
Elena
E
Freschi
Massimo
M
Bertilaccio
Maria T S
MT
Hess-Michelini
Rodrigo
R
Doglioni
Claudio
C
Bellone
Matteo
M
D000230:Adenocarcinoma / Q000276:immunology* / Q000473:pathology; D000375:Aging / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015704:CD4 Antigens / Q000032:analysis; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation; D051858:Forkhead Transcription Factors / Q000032:analysis; D007108:Immune Tolerance; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008198:Lymph Nodes / Q000276:immunology; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D014611:Vaccination
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit