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 3

Expression of PD-L1 by NK cell–sensitive, T cell–resistant tumor cells promotes more aggressive tumor growth in vivo.

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Expression of PD-L1 by NK cell–sensitive, T cell–resistant tumor cells p...
(A) RMA-S cells were transduced with PD-L1 expression vector or an empty control vector. G418-resistant transductants were selected. Transduced cells, as well as untransduced RMA-S cells, were injected into C57BL/6J mice (106 cells/mouse s.c.), and tumor growth was monitored. Tumor volumes (mean ± SEM) are shown for each time point. The experiment shown is representative of 3 performed. n = 5–6. *P < 0.05, 2-way ANOVA. Survival (B) and in vivo tumor growth (mean ± SEM) (C) were assessed after s.c. injection of 1 × 106 RMA-S or RMA-S–Pdl1 tumor cells in C57BL/6J mice. Where indicated, NK cells were depleted by injecting NK1.1 antibody. The results depicted are representative of 8 independent experiments, 2 of which included NK cell–depleted mice for comparison. In the experiment shown, n = 6–7 per group. **P < 0.01, log-rank (Mantel-Cox) test (B); 2-way ANOVA test (C). (D) 106 RMA-S or RMA-S–Pdl1 cells were injected s.c. into Rag2–/–Il2rg–/– mice, and tumor growth was assessed. Tumor volumes (mean ± SEM) are shown. Experiment shown is representative of 3 independent experiments, n = 4/group. (E) 106 RMA or RMA-Pdl1 tumor cells were injected s.c. into C57BL/6J mice, and tumor growth was monitored. Tumor volumes (mean ± SEM) are shown. Experiment shown is representative of 2 performed. n = 5 for RMA group and n = 6 for RMA-Pdl1 group.