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

Publication date: Available online 3 April 2018
Source:Immunity
Author(s): Jing Li, Younghee Lee, Yanjian Li, Yu Jiang, Huiping Lu, Wenjuan Zang, Xiaohong Zhao, Liguo Liu, Yang Chen, Haidong Tan, Zhiying Yang, Michael Q. Zhang, Tak W. Mak, Ling Ni, Chen Dong
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.

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Teaser

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.


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