title: Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors.
abstract: Tumor progression is facilitated by regulatory T cells (Treg) and restricted by effector T cells. In this study, we document parallel regulation of CD8(+) T cells and Foxp3(+) Tregs by programmed death-1 (PD-1, PDCD1). In addition, we identify an additional role of CTL antigen-4 (CTLA-4) inhibitory receptor in further promoting dysfunction of CD8(+) T effector cells in tumor models (CT26 colon carcinoma and ID8-VEGF ovarian carcinoma). Two thirds of CD8(+) tumor-infiltrating lymphocytes (TIL) expressed PD-1, whereas one third to half of CD8(+) TIL coexpressed PD-1 and CTLA-4. Double-positive (PD-1(+)CTLA-4(+)) CD8(+) TIL had characteristics of more severe dysfunction than single-positive (PD-1(+) or CTLA-4(+)) TIL, including an inability to proliferate and secrete effector cytokines. Blockade of both PD-1 and CTLA-4 resulted in reversal of CD8(+) TIL dysfunction and led to tumor rejection in two thirds of mice. Double blockade was associated with increased proliferation of antigen-specific effector CD8(+) and CD4(+) T cells, antigen-specific cytokine release, inhibition of suppressive functions of Tregs, and upregulation of key signaling molecules critical for T-cell function. When used in combination with GVAX vaccination (consisting of granulocyte macrophage colony-stimulating factor-expressing irradiated tumor cells), inhibitory pathway blockade induced rejection of CT26 tumors in 100% of mice and ID8-VEGF tumors in 75% of mice. Our study indicates that PD-1 signaling in tumors is required for both suppressing effector T cells and maintaining tumor Tregs, and that PD-1/PD-L1 pathway (CD274) blockade augments tumor inhibition by increasing effector T-cell activity, thereby attenuating Treg suppression.
authors: Ovarian Cancer Research Center; Department of Obstetrics & Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Jaikumar
authors: J
authors: Duraiswamy
authors: Karen M
authors: KM
authors: Kaluza
authors: Gordon J
authors: GJ
authors: Freeman
authors: George
authors: G
authors: Coukos
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology / Q000494:pharmacology; D060890:B7-H1 Antigen / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D003131:Combined Modality Therapy; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; C498919:Cd274 protein, mouse; D016207:Cytokines; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor
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