CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells.
CTL-associated antigen 4 (CTLA4) blockade releases inhibitory controls on T cell activation and proliferation, inducing antitumor immunity in both preclinical and early clinical trials. We examined the mechanisms of action of anti-CTLA4 and a GM-CSF-transduced tumor cell vaccine (Gvax) and their impact on the balance of effector T cells (Teffs) and Tregs in an in vivo model of B16/BL6 melanoma. Tumor challenge increased the frequency of Tregs in lymph nodes, and untreated tumors became infiltrated by CD4+Foxp3- and CD4+Foxp3+ T cells but few CD8+ T cells. Anti-CTLA4 did not deplete Tregs or permanently impair their function but acted in a cell-intrinsic manner on both Tregs and Teffs, allowing them to expand, most likely in response to self antigen. While Gvax primed the tumor-reactive Teff compartment, inducing activation, tumor infiltration, and a delay in tumor growth, the combination with CTLA4 blockade induced greater infiltration and a striking change in the intratumor balance of Tregs and Teffs that directly correlated with tumor rejection. The data suggest that Tregs control both CD4+ and CD8+ T cell activity within the tumor, highlight the importance of the intratumor ratio of effectors to regulators, and demonstrate inversion of the ratio and correlation with tumor rejection during Gvax/anti-CTLA4 immunotherapy.
Quezada
Sergio A
SA
Howard Hughes Medical Institute, Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Peggs
Karl S
KS
Curran
Michael A
MA
Allison
James P
JP
D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology / Q000627:therapeutic use; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000627:therapeutic use; D007167:Immunotherapy; D008198:Lymph Nodes / Q000166:cytology; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D015704:CD4 Antigens; D016827:CD8 Antigens; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016178:Granulocyte-Macrophage Colony-Stimulating Factor