期刊
CANCER IMMUNOLOGY RESEARCH
卷 7, 期 8, 页码 1293-1306出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-18-0885
关键词
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资金
- CAMS CIFMS, China [2018-I2M-2-002, 2017PT31043]
- Medical Research Council, United Kingdom [MR/L018942/1]
- Medical Research Council, United Kingdom (MRC Human Immunology Unit Core)
- Malaysia's King Scholarship
- National Institute of Health Research (NIHR) Oxford Biomedical Research Centre (BRC
- Molecular Diagnostics Theme/Multimodal Pathology Subtheme)
- NIHR Oxford BRC (Molecular Diagnostics Theme/Multimodal Pathology Subtheme)
- MRC [G1000800, MC_UU_00008/7, MR/K01577X/1, G0800158, MC_UU_12010/7, G0600520, MC_PC_15002, MC_UU_00008/1, MC_UU_12010/1, MC_U137884181, G1001046, G0501975, MR/L018942/1, MR/S036377/1] Funding Source: UKRI
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 thorn 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 thorn 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 IFNg-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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