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

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 5

Cell autonomous IL-36 signaling is a potent activator of neutrophils.

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Cell autonomous IL-36 signaling is a potent activator of neutrophils. (A...
(A) IL-36R expression analysis on neutrophils and monocytes from bone marrow by flow cytometry using anti-IL-36R antibody (catalog 7501, ProSci). Cells were gated on CD11b+Ly6G+ for neutrophils and CD11b+Ly6C+ for monocytes. Histograms for WT and IL-36R–KO and mean florescence intensity (MFI) calculated from triplicates and 2 independent experiments is shown in the bar graph. MFI was normalized to that in KO cells. (B and C) Western blot analysis showing IL-36–mediated signaling in neutrophils treated with 100 ng/mL rmIL-36γ in WT and IL-36R–KO mice (B) NF-κB signaling. (C) p38 MAPK signaling. Hsp90 was used as loading control. (D) Number of differentially expressed genes in various innate immune cells isolated from spleen and bone marrow of WT C57BL/6 mice upon treatment with 500 ng/mL rmIL-36γ for 6 hours. (E and F) Pathway analysis of differentially expressed genes in neutrophils isolated from bone marrow of WT C57BL/6 mice upon treatment with rmIL-36γ for 6 hours showing pathways that (E) affect neutrophil-intrinsic biology and (F) modulate various other immune cells. (G) Production of proinflammatory cytokines and chemokines by neutrophils isolated from bone marrow of WT C57BL/6 mice and treated with 500 ng/mL rmIL-36γ for 24 hours. Cytokines and chemokines were detected using a multiplexed MSD kit. (H) IL-36–mediated activation of neutrophils, as depicted by change in CD62L expression with rmIL-36γ. Representative dot plots and average percentage positive cells are shown in the bar graphs. Data are shown as mean ± SEM. (F and G) Unpaired 2-tailed Mann-Whitney t test. ****P < 0.0001. Data are representative of 1 (D–F), 2 (A, B, C, and G), 3 (H) independent experiments.