Co-inhibitory Molecule B7 Superfamily Member 1 Expressed by Tumor-Infiltrating Myeloid Cells Induces Dysfunction of Anti-tumor CD8+ T Cells

• Published in: Immunity (Cambridge, Mass.) Mass.), 2018-04, Vol.48 (4), p.773-786.e5
• Main Authors: Li, Jing, Lee, Younghee, Li, Yanjian, Jiang, Yu, Lu, Huiping, Zang, Wenjuan, Zhao, Xiaohong, Liu, Liguo, Chen, Yang, Tan, Haidong, Yang, Zhiying, Zhang, Michael Q., Mak, Tak W., Ni, Ling, Dong, Chen
• Format: Article
• Language: English
• Subjects: Antigens; Apoptosis; B7 antigen; B7S1; Cancer immunotherapy; CD8 antigen; Cell activation; combinational blockade of immune checkpoints; Combinatorial analysis; Cytotoxicity; Eomes; Epigenetics; Exhaustion; Gene expression; Hepatocellular carcinoma; Immune response; Immunotherapy; Infections; Liver cancer; Lymphocytes; Lymphocytes T; Melanoma; Molecular modelling; Mucin; Myeloid cells; PD-1; PD-1 protein; PD-L1 protein; Statistical analysis; T cell exhaustion; Tumor cells; tumor immunity; Tumors
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2018.03.018

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. [Display omitted] •Upregulated B7S1 expression on APCs correlates with CD8+ T dysfunction in human cancer•Inhibition of B7S1 promotes CD8+ T cell-mediated tumor immunity in murine cancer models•B7S1, via its receptor expressed on early activated CD8+ TILs, drives T cell exhaustion•Co-blockade of B7S1 and PD-1 can more potently reinvigorate anti-tumor responses Mechanisms driving T cell exhaustion have not been understood. Li et al. demonstrate that B7S1 on tumor-infiltrating myeloid cells initiates exhaustion of activated CD8+ TILs through upregulating Eomes, thus proposing B7S1 as a promising target to enhance the efficacy of anti-PD-1 therapy.