Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-05, Vol.112 (21), p.6682-6687
• Main Authors: Liu, Jun, Yuan, Ying, Chen, Wenna, Putra, Juan, Suriawinata, Arief A., Schenk, Austin D., Miller, Halli E., Guleria, Indira, Barth, Richard J., Huang, Yina H., Wang, Li
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - administration & dosage; Antigens - administration & dosage; B7-H1 Antigen - deficiency; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Biological Sciences; Female; Immune system; Immune Tolerance; Ligands; Lymphocyte Activation; Lymphocytes; Male; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Monoclonal antibodies; Neoplasms, Experimental - immunology; Programmed Cell Death 1 Receptor - deficiency; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; Proteins; Rodents; T-Lymphocytes - immunology; Transgenic animals
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1420370112

Significance Multiple immune-checkpoint proteins, such as programmed death 1 (PD-1), LAG3, and TIM3, are coexpressed on immune cells and functionally synergize with each other. V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a recently identified immune-checkpoint molecule that suppresses T-cell activation. This study establishes that VISTA and PD-1 exert nonredundant immune regulatory functions and synergistically regulate T-cell responses. Combinatorial treatment using VISTA- and PD-ligand 1-specific monoclonal antibodies achieved synergistic therapeutic efficacy in murine tumor models. This study critically advances our knowledge of the immune regulatory function of VISTA and provides a rationale for targeting both VISTA and PD-1 to more effectively treat T-cell-regulated diseases such as cancer. V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a negative immune-checkpoint protein that suppresses T-cell responses. To determine whether VISTA synergizes with another immune-checkpoint, programmed death 1 (PD-1), this study characterizes the immune responses in VISTA-deficient, PD-1-deficient (KO) mice and VISTA/PD-1 double KO mice. Chronic inflammation and spontaneous activation of T cells were observed in both single KO mice, demonstrating their nonredundancy. However, the VISTA/PD-1 double KO mice exhibited significantly higher levels of these phenotypes than the single KO mice. When bred onto the 2D2 T-cell receptor transgenic mice, which are predisposed to development of inflammatory autoimmune disease in the CNS, the level of disease penetrance was significantly enhanced in the double KO mice compared with in the single KO mice. Consistently, the magnitude of T-cell response toward foreign antigens was synergistically higher in the VISTA/PD-1 double KO mice. A combinatorial blockade using monoclonal antibodies specific for VISTA and PD-L1 achieved optimal tumor-clearing therapeutic efficacy. In conclusion, our study demonstrates the nonredundant role of VISTA that is distinct from the PD-1/PD-L1 pathway in controlling T-cell activation. These findings provide the rationale to concurrently target VISTA and PD-1 pathways for treating T-cell-regulated diseases such as cancer.