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Abstract NKG2A and its co-receptor, CD94, are expressed on the surface of NK cells, and function to send inhibitory signals to NK cells upon recognition of the HLA-E complex on adjacent cells. Blockade of the NKG2A/CD94 complex is a promising strategy for cancer immunotherapy, due to the potential to trigger NK-mediated tumor killing. Previously, we generated humanized NKG2A/CD94 mice for testing novel therapeutics targeting human NKG2A/CD94. To explore the potential that this complex could be targeted as part of a novel combination therapy, we crossed humanized NKG2A/CD94 mice with humanized PD-1/PD-L1 mice, which were previously engineered to express the extracellular regions of human PD-1/PD-L1. Flow cytometric data from splenocytes isolated from the quadruple humanized mice confirmed expression of human NKG2A and CD94 in NK cells and activated CD8 T cells, as well as PD-1/PD-L1 on the surface of T cells. To test the efficacy of antibodies targeting these checkpoints in vivo, B-hHLA-E plus/hPD-L1 MC38 colon cancer cells were subcutaneously implanted into the quadruple humanized mice and treated with antibodies targeting human NKG2A, human PD-L1, or both antibodies. Results indicate that the combination therapy significantly reduced tumor growth when compared to NKG2A single antibody treatment. Together, these data suggest that humanized PD-1/PD-L1/CD94/NKG2A mice are a validated model for further evaluation of novel combination therapies. Citation Format: Fang He, Jiangfeng Yuan, Yawen Shan, Huwatibieke Bahetiyaer, Qingqing Xu, Jenna Frame, Qingcong Lin, Xiaofei Zhou, Chengzhang Shang. Generation of humanized PD-1/PD-L1/CD94/NKG2A mice for evaluating novel combination therapies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 116.
He et al. (2024) studied this question.