Li et al. show that the molecule B7S1, expressed on APCs and some tumor cells, is an inhibitory ligand which acts to suppress activated CD8+ T cells via Eomes overexpression and other pathways that largely overlap with PD-1, possibly explaining the low response rate in patients treated with PD-1 blockade. Blockade of both B7S1 and PD-1 synergistically improved the antitumor response in mice. Coexpression of PD-1 and the putative B7S1 receptor on CD8+ TILs indicated an activated, transitional state, while coexpression of PD-1 and TIM-3 was associated with exhaustion.
The molecular mechanisms whereby CD8(+) T cells become "exhausted" in the tumor microenvironment remain unclear. Programmed death ligand-1 (PD-L1) is upregulated on tumor cells and PD-1-PD-L1 blockade has significant efficacy in human tumors; however, most patients do not respond, suggesting additional mechanisms underlying T cell exhaustion. B7 superfamily member 1 (B7S1), also called B7-H4, B7x, or VTCN1, negatively regulates T cell activation. Here we show increased B7S1 expression on myeloid cells from human hepatocellular carcinoma correlated with CD8(+) T cell dysfunction. B7S1 inhibition suppressed development of murine tumors. Putative B7S1 receptor was co-expressed with PD-1 but not T cell immunoglobulin and mucin-domain containing-3 (Tim-3) at an activated state of early tumor-infiltrating CD8(+) T cells, and B7S1 promoted T cell exhaustion, possibly through Eomes overexpression. Combinatorial blockade of B7S1 and PD-1 synergistically enhanced anti-tumor immune responses. Collectively, B7S1 initiates dysfunction of tumor-infiltrating CD8(+) T cells and may be targeted for cancer immunotherapy.
Author Info: (1) Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. (2) Departments of Immunology, MD Anderson Cancer Center, Houston, TX 77054, USA. (
Author Info: (1) Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. (2) Departments of Immunology, MD Anderson Cancer Center, Houston, TX 77054, USA. (3) MOE Key Laboratory of Bioinformatics; Bioinformatics Division and Center for Synthetic & Systems Biology, TNLIST; School of Medicine, Tsinghua University, Beijing 100084, China. (4) Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. (5) Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. (6) Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. (7) Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. (8) Department of Hepatobiliary Surgery, China-Japan Friendship Hospital, Beijing 100029, China. (9) MOE Key Laboratory of Bioinformatics; Bioinformatics Division and Center for Synthetic & Systems Biology, TNLIST; School of Medicine, Tsinghua University, Beijing 100084, China. (10) Department of Hepatobiliary Surgery, China-Japan Friendship Hospital, Beijing 100029, China. (11) Department of Hepatobiliary Surgery, China-Japan Friendship Hospital, Beijing 100029, China. (12) MOE Key Laboratory of Bioinformatics; Bioinformatics Division and Center for Synthetic & Systems Biology, TNLIST; School of Medicine, Tsinghua University, Beijing 100084, China; Department of Biological Sciences, Center for Systems Biology, The University of Texas, Dallas, TX 75080, USA. (13) The Campbell Family Cancer Research Institute and University Health Network, Toronto, ON M5G 2C1, Canada. (14) Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. (15) Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China; Beijing Key Lab for Immunological Research on Chronic Diseases, Beijing 100084, China. Electronic address: chendong@tsinghua.edu.cn.
