NKG2A Blockade Potentiates CD8 T Cell Immunity Induced by Cancer Vaccines

• Published in: Cell Vol. 175; no. 7; pp. 1744 - 1755.e15
• Main Authors: van Montfoort, Nadine, Borst, Linda, Korrer, Michael J., Sluijter, Marjolein, Marijt, Koen A., Santegoets, Saskia J., van Ham, Vanessa J., Ehsan, Ilina, Charoentong, Pornpimol, André, Pascale, Wagtmann, Nicolai, Welters, Marij J.P., Kim, Young J., Piersma, Sytse J., van der Burg, Sjoerd H., van Hall, Thorbald
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13-12-2018
• Subjects: acquired resistance; Animals; Antibodies, Neoplasm - immunology; Antigens, CD - immunology; cancer vaccines; Cancer Vaccines - immunology; Cancer Vaccines - pharmacology; CD8 T cells; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Cell Line, Tumor; Histocompatibility Antigens Class I - immunology; HLA-E; HLA-E Antigens; Humans; IFN-γ; immune checkpoints; Immunity, Cellular; Integrin alpha Chains - immunology; Mice; mouse tumor models; natural killer cells; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - immunology; Neoplasms, Experimental - immunology; Neoplasms, Experimental - pathology; Neoplasms, Experimental - therapy; NK Cell Lectin-Like Receptor Subfamily C - antagonists & inhibitors; NK Cell Lectin-Like Receptor Subfamily C - immunology; NKG2A; Qa-1; Vaccination; natural killer cells; Qa-1; IFN-γ; cancer vaccines; NKG2A; mouse tumor models; CD8 T cells; acquired resistance; HLA-E; immune checkpoints
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2018.10.028

Tumor-infiltrating CD8 T cells were found to frequently express the inhibitory receptor NKG2A, particularly in immune-reactive environments and after therapeutic cancer vaccination. High-dimensional cluster analysis demonstrated that NKG2A marks a unique immune effector subset preferentially co-expressing the tissue-resident CD103 molecule, but not immune checkpoint inhibitors. To examine whether NKG2A represented an adaptive resistance mechanism to cancer vaccination, we blocked the receptor with an antibody and knocked out its ligand Qa-1b, the conserved ortholog of HLA-E, in four mouse tumor models. The impact of therapeutic vaccines was greatly potentiated by disruption of the NKG2A/Qa-1b axis even in a PD-1 refractory mouse model. NKG2A blockade therapy operated through CD8 T cells, but not NK cells. These findings indicate that NKG2A-blocking antibodies might improve clinical responses to therapeutic cancer vaccines.
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•Checkpoint NKG2A is expressed on intratumoral CD103+ effector CD8 T cells•NKG2A is upregulated on CD8 T cells in tumors by cancer vaccines•IFN-γ induces the ligand Qa-1/HLA-E on tumor cells, mediating adaptive resistance•Blocking NKG2A turns cancer vaccines into effective therapies
Blocking the function of the NKG2A inhibitory receptor, as well as its ligand, promotes robust anti-tumor immunity in a number of animal tumor models, including one refractory to PD-1 blockade.