1. Autonomous IL-36R signaling in neutrophils activates potent antitumor effector functions
- Author
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Roy, Sumedha, Fitzgerald, Karen, Lalani, Almin, Lai, Chin-Wen, Kim, Aeryon, Kim, Jennie, Ou, Peiqi, Mirsoian, Annie, Liu, Xian, Ramrakhiani, Ambika, Zhao, Huiren, Zhou, Hong, Xu, Haoda, Meisen, Hans, Li, Chi-Ming, Lugt, Bryan Vander, Thibault, Steve, Tinberg, Christine E., DeVoss, Jason, Egen, Jackson, Wu, Lawren C., and Noubade, Rajkumar
- Subjects
Tumors -- Care and treatment -- Development and progression ,Immune response -- Health aspects ,Immunotherapy -- Methods -- Physiological aspects ,Neutrophils -- Health aspects -- Physiological aspects ,Cellular signal transduction -- Health aspects ,Interleukins -- Health aspects -- Physiological aspects ,Health care industry - 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., Introduction Immunotherapy, particularly checkpoint inhibitors such as anti-PD(L)1, has revolutionized treatment options for patients with cancer. However, responses are limited to only subsets of patients and indications (1-3). Intratumoral T [...]
- Published
- 2023
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