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 4

PD-1 suppresses NK cell–mediated control of B16 colonization in the lungs.

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PD-1 suppresses NK cell–mediated control of B16 colonization in the lung...
(A) B16 cells were transduced with a retroviral vector encoding mouse PD-L1 and sorted for PD-L1 expression. (B) C57BL/6J mice were injected i.v. with 0.25 × 106 B16 tumor cells or saline solution. Mice were sacrificed at terminal stage of disease, and PD-1 expression was assessed by flow cytometry on splenic or lung NK cells. NK cells were gated as viable CD45+Ter119–CD3–CD19–F4/80–NK1.1+NKp46+. Student’s t test. (C–F) Kaplan-Meier analyses of C57BL/6J mice injected i.v. with 5,000 (C, D) or 20,000 (E, F) B16 or B16-Pdl1 cells. For D and F, mice were NK depleted with NK1.1 antibody. Data for C and D represent results pooled from 2 experiments, with n = 7–15/group. Data for E and F represent results pooled from 2 experiments, with n = 8–12/combined group. log-rank (Mantel-Cox) test. (G) C57BL/6 mice were injected i.v. with 2 × 104 B16 or B16-Pdl1 cells. Twenty-one days later, the presence of tumors in the lungs was assessed by macroscopic examination. Data are from 2 independent experiments with n = 12–13/combined group. Fisher’s exact test. (H) C57BL/6 mice were injected i.v. with 20,000 B16 or B16-Pdl1 cells. Twenty-one days later, tumor burden in the lungs was assessed by qRT-PCR of transcripts of the melanoma-specific gene Gp100. H shows a combination of 2 independent experiments with n = 9–10/group. Mann-Whitney U test.