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Autonomous IL-36R signaling in neutrophils activates potent antitumor effector functions
Sumedha Roy, … , Lawren C. Wu, Rajkumar Noubade
Sumedha Roy, … , Lawren C. Wu, Rajkumar Noubade
Published June 15, 2023
Citation Information: J Clin Invest. 2023;133(12):e162088. https://doi.org/10.1172/JCI162088.
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Research Article Immunology Oncology Article has an altmetric score of 3

Autonomous IL-36R signaling in neutrophils activates potent antitumor effector functions

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Abstract

While the rapid advancement of immunotherapies has revolutionized cancer treatment, only a small fraction of patients derive clinical benefit. Eradication of large, established tumors appears to depend on engaging and activating both innate and adaptive immune system components to mount a rigorous and comprehensive immune response. Identifying such agents is a high unmet medical need, because they are sparse in the therapeutic landscape of cancer treatment. Here, we report that IL-36 cytokine can engage both innate and adaptive immunity to remodel an immune-suppressive tumor microenvironment (TME) and mediate potent antitumor immune responses via signaling in host hematopoietic cells. Mechanistically, IL-36 signaling modulates neutrophils in a cell-intrinsic manner to greatly enhance not only their ability to directly kill tumor cells but also promote T and NK cell responses. Thus, while poor prognostic outcomes are typically associated with neutrophil enrichment in the TME, our results highlight the pleiotropic effects of IL-36 and its therapeutic potential to modify tumor-infiltrating neutrophils into potent effector cells and engage both the innate and adaptive immune system to achieve durable antitumor responses in solid tumors.

Authors

Sumedha Roy, Karen Fitzgerald, Almin Lalani, Chin-Wen Lai, Aeryon Kim, Jennie Kim, Peiqi Ou, Annie Mirsoian, Xian Liu, Ambika Ramrakhiani, Huiren Zhao, Hong Zhou, Haoda Xu, Hans Meisen, Chi-Ming Li, Bryan Vander Lugt, Steve Thibault, Christine E. Tinberg, Jason DeVoss, Jackson Egen, Lawren C. Wu, Rajkumar Noubade

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Figure 7

IL-36–activated neutrophils modulate NK cell cytotoxicity and T cell proliferation.

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IL-36–activated neutrophils modulate NK cell cytotoxicity and T cell pro...
(A and B) Cell killing of MC38 cells expressing luciferase (MC38-Luc) by (A) NK cells alone, neutrophils alone or combination of NK cells, and neutrophils when treated with 500 ng/mL rmIL-36γ or (B) NK cells alone, supernatant from IL-36–treated neutrophils alone, or combination of NK cells and supernatant. The E:T ratio for NK cells was 10:1 and for neutrophils it was 2:1. Data are represented as luciferase signal relative to MC38-Luc cells cultured alone, without the presence of NK cells and neutrophils. (C) Anti-CD3/CD28 stimulated proliferation of WT or IL-36R–KO T cells cocultured with either WT neutrophils or IL-36R–KO neutrophils for 72 hours. All conditions contained 500 ng/mL rmIL-36γ and 1 μM of CpG class C. Representative histograms are shown on the left, and average proliferation is shown in the bar graph on right. (D) OT-1 T cell proliferation for 48 hours in the presence of bone marrow neutrophils that were previously either untreated or prestimulated with 500 ng/mL of rmIL-36γ for 2 h and then fed with OVA protein. Representative graphs are shown on the left and average proliferation is shown in the bar graph. ConA is used as positive control for T cell proliferation. (E) IFN-γ ELISPOT assay using splenocytes from MC38 tumor-bearing mice cocultured with neutrophils that were previously either untreated or treated with 500 ng/mL rmIL-36γ for 2 hours and fed with MC38 tumor cell lysate or neoantigen Adpgk peptide. Number of IFN-γ–positive spots after 24 hours is shown. Data are shown as mean ± SEM. (E) Unpaired 2-tailed Mann-Whitney t test. (A–D) One-way ANOVA followed by Tukey’s multiple comparison. *P < 0.05, ***P < 0.001, ****P < 0.0001. neut, neutrophil. Data are representative of 2 (C–E) and 3 (A and B) independent experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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