Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade

TLDR

Checkpoint blockade targeting the PD‑1/PD‑L1 axis has yielded remarkable cancer treatment results, yet tumors with low MHC expression still respond, implying that immune cells beyond cytotoxic T cells may contribute. The study investigates how PD‑1/PD‑L1 blockade affects NK cells in mouse cancer models. The authors used several mouse tumor models to assess PD‑1 and PD‑L1 expression on NK cells and measured NK cell responses after blockade. PD‑1/PD‑L1 blockade provokes a robust NK cell response that is essential for the therapy’s full efficacy, with PD‑1 expressed on activated NK cells and PD‑L1 on tumor cells dampening NK activity and promoting aggressive tumors.

Abstract

Checkpoint blockade immunotherapy targeting the PD-1/PD-L1 inhibitory axis has produced remarkable results in the treatment of several types of cancer. Whereas cytotoxic T cells are known to provide important antitumor effects during checkpoint blockade, certain cancers with low MHC expression are responsive to therapy, suggesting that other immune cell types may also play a role. Here, we employed several mouse models of cancer to investigate the effect of PD-1/PD-L1 blockade on NK cells, a population of cytotoxic innate lymphocytes that also mediate antitumor immunity. We discovered that PD-1 and PD-L1 blockade elicited a strong NK cell response that was indispensable for the full therapeutic effect of immunotherapy. PD-1 was expressed on NK cells within transplantable, spontaneous, and genetically induced mouse tumor models, and PD-L1 expression in cancer cells resulted in reduced NK cell responses and generation of more aggressive tumors in vivo. PD-1 expression was more abundant on NK cells with an activated and more responsive phenotype and did not mark NK cells with an exhausted phenotype. These results demonstrate the importance of the PD-1/PD-L1 axis in inhibiting NK cell responses in vivo and reveal that NK cells, in addition to T cells, mediate the effect of PD-1/PD-L1 blockade immunotherapy.