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. 2019 Aug;7(8):1293-1306.
doi: 10.1158/2326-6066.CIR-18-0885. Epub 2019 Jun 18.

Enriched HLA-E and CD94/NKG2A Interaction Limits Antitumor CD8+ Tumor-Infiltrating T Lymphocyte Responses

Megat Abd Hamid  1   2 , Ruo-Zheng Wang  3   4 , Xuan Yao  1   2 , Peiwen Fan  5   4 , Xi Li  1   2 , Xue-Mei Chang  5   4 , Yaning Feng  5   4 , Stephanie Jones  6 , David Maldonado-Perez  6   7 , Craig Waugh  8 , Clare Verrill  6   7 , Alison Simmons  1   2 , Vincenzo Cerundolo  1   2 , Andrew McMichael  1 , Christopher Conlon  1 , Xiyan Wang  2   4 , Yanchun Peng  1   2 , Tao Dong  9   2   5
Affiliations

Enriched HLA-E and CD94/NKG2A Interaction Limits Antitumor CD8+ Tumor-Infiltrating T Lymphocyte Responses

Megat Abd Hamid et al. Cancer Immunol Res. 2019 Aug.

Abstract

Immunotherapy treatments with anti-PD-1 boost recovery in less than 30% of treated cancer patients, indicating the complexity of the tumor microenvironment. Expression of HLA-E is linked to poor clinical outcomes in mice and human patients. However, the contributions to immune evasion of HLA-E, a ligand for the inhibitory CD94/NKG2A receptor, when expressed on tumors, compared with adjacent tissue and peripheral blood mononuclear cells, remains unclear. In this study, we report that epithelial-derived cancer cells, tumor macrophages, and CD141+ conventional dendritic cells (cDC) contributed to HLA-E enrichment in carcinomas. Different cancer types showed a similar pattern of enrichment. Enrichment correlated to NKG2A upregulation on CD8+ tumor-infiltrating T lymphocytes (TIL) but not on CD4+ TILs. CD94/NKG2A is exclusively expressed on PD-1high TILs while lacking intratumoral CD103 expression. We also found that the presence of CD94/NKG2A on human tumor-specific T cells impairs IL2 receptor-dependent proliferation, which affects IFNγ-mediated responses and antitumor cytotoxicity. These functionalities recover following antibody-mediated blockade in vitro and ex vivo Our results suggest that enriched HLA-E:CD94/NKG2A inhibitory interaction can impair survival of PD-1high TILs in the tumor microenvironment.

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