Depletion of tumor-induced Treg prior to reconstitution rescues enhanced priming of tumor-specific, therapeutic effector T cells in lymphopenic hosts.
We reported previously that vaccination of reconstituted, lymphopenic mice resulted in a higher frequency of tumor-specific effector T cells with therapeutic activity than vaccination of normal mice. Here, we show that lymphopenic mice reconstituted with spleen cells from tumor-bearing mice (TBM), a situation that resembles the clinical condition, failed to generate tumor-specific T cells with therapeutic efficacy. However, depletion of CD25(+) Treg from the spleen cells of TBM restored tumor-specific priming and therapeutic efficacy. Adding back TBM CD25(+) Treg to CD25(-) naïve and TBM donor T cells prior to reconstitution confirmed their suppressive role. CD25(+) Treg from TBM prevented priming of tumor-specific T cells since subsequent depletion of CD4(+) T cells did not restore therapeutic efficacy. This effect may not be antigen-specific as three histologically distinct tumors generated CD25(+) Treg that could suppress the T-cell immune response to a melanoma vaccine. Importantly, since ex vivo depletion of CD25(+) Treg from TBM spleen cells prior to reconstitution and vaccination fully restored the generation of therapeutic effector T cells, even in animals with established tumor burden, we have initiated a translational clinical trial of this strategy in patients with metastatic melanoma.
Laboratory of Molecular and Tumor Immunology, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, OR 97213, USA.
Christian H
CH
Poehlein
Daniel P
DP
Haley
Edwin B
EB
Walker
Bernard A
BA
Fox
D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008212:Lymphocyte Depletion; D008231:Lymphopenia / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D019496:Cancer Vaccines; D053645:Interleukin-2 Receptor alpha Subunit