Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade
Joy Hsu, … , David H. Raulet, Michele Ardolino
Joy Hsu, … , David H. Raulet, Michele Ardolino
Published September 10, 2018
Citation Information: J Clin Invest. 2018;128(10):4654-4668. https://doi.org/10.1172/JCI99317.
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Research Article Immunology

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

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.

Authors

Joy Hsu, Jonathan J. Hodgins, Malvika Marathe, Chris J. Nicolai, Marie-Claude Bourgeois-Daigneault, Troy N. Trevino, Camillia S. Azimi, Amit K. Scheer, Haley E. Randolph, Thornton W. Thompson, Lily Zhang, Alexandre Iannello, Nikhita Mathur, Karen E. Jardine, Georgia A. Kirn, John C. Bell, Michael W. McBurney, David H. Raulet, Michele Ardolino

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Figure 5

PD-L1 expression by CT26 tumor cells prevents tumor rejection mediated by NK cells and CD8+ T cells.

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PD-L1 expression by CT26 tumor cells prevents tumor rejection mediated b...
(A) PD-L1 expression by CT26 cell variants. Cells were untreated or treated with 20 ng/ml IFN-γ for 48 hours, and PD-L1 expression was analyzed by flow cytometry. Top panel: comparison of CT26 and CT26-Pdl1–/– cells. Lower panel: comparison of CT26-Pdl1–/– cells transduced with a PD-L1 expression vector or with an empty vector. WT CT26 cells transduced with empty vector served as a control. (B, C) In vivo growth of CT26 or CT26-Pdl1–/– tumors was assessed after s.c. injection of 0.5 × 106 cells in BALB/cJ mice. Some mice were depleted of NK cells (with asialo GM-1 antibody), CD8+ T cells (with CD8α-specific 2.43 antibody), or both before tumor cell injection. Tumor volumes (mean ± SEM) are shown. For B, 2-way ANOVA tests were used to compare CT26-Pdl1–/–/undepleted mice with either CT26/undepleted mice (P < 0.01), CT26-Pdl1–/–/NK-depleted mice (P < 0.0001), or CT26-Pdl1–/–/CD8-depleted mice (P < 0.01). Two-way ANOVA tests were also used to compare CT26-Pdl1–/–/NK&CD8-depleted mice to either CT26-Pdl1–/–/CD8-depleted mice (P < 0.05) or CT26-Pdl1–/–/NK-depleted mice (P = 0.0599). For C, none of the differences were significant. Data from B and C are from the same experiment, which is representative of 2 performed. n = 8 for the experiment shown. (D) 0.2 × 106 CT26-Pdl1–/– cells transduced with an empty vector or a PD-L1 expression vector or CT26 WT cells transduced with an empty vector were injected s.c. in BALB/cJ mice, and tumor progression was assessed. Experiment depicted is representative of 3 performed. n = 3–4 mice/group. *P < 0.05; ***P < 0.001, 2-way ANOVA.