Abstract A97: The inhibitory receptor NKG2A acts as a checkpoint on CD8 T cells in the context of cancer vaccines

We previously demonstrated that high HLA-E expression in ovarian carcinoma and NSCLC may neutralize the survival benefit of T-cell infiltration, suggesting NKG2A could represent an immune checkpoint. Here, we demonstrate higher frequencies of NKG2A+CD8+ T cells in TIL samples obtained from human HNSCC biopsies in patients with measurable immune reactivity to HPV16-viral antigens. CyTOF analysis suggested that this T-cell subset harbored an CD103+ effector phenotype. In mouse tumor models, therapeutic cancer vaccines increased the frequency of NKG2A+-positive CD8+ TIL up to 80%. Expression of Qa-1, the mouse homologue of HLA-E, on tumor cells also increased after cancer vaccinations. In vitro studies revealed that upregulation of Qa-1 was mediated by T cell-derived IFNγ. Blockade of this inhibiting NKG2A-Qa-1 axis by antibody improved the T-cell mediated rejection of tumors and, in addition, genetic knockdown of Qa-1 in three different tumor models recapitulated this finding. Blocking of NKG2A as a stand-alone treatment was not effective, indicating that NKG2A constitutes an adaptive resistance mechanism in response to CD8 T-cell activation. In conclusion, NKG2A is enriched on CD8+ TIL and functions as an immune checkpoint that restrains therapeutic efficacy of cancer vaccines. Citation Format: Thorbald van Hall, Nadine van Montfoort, Linda Borst, Michael J. Korrer, Young Kim, Pascale Andre, Nicolai Wagtmann, Sytse Piersma, Sjoerd H. van der Burg. The inhibitory receptor NKG2A acts as a checkpoint on CD8 T cells in the context of cancer vaccines [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A97.