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.
Poehlein
Christian H
CH
Laboratory of Molecular and Tumor Immunology, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, OR 97213, USA.
Haley
Daniel P
DP
Walker
Edwin B
EB
Fox
Bernard A
BA
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