Neutrophils Deficient in Innate Suppressor IRAK-M Enhances Anti-tumor Immune Responses.

Yao Zhang, Na Diao, Christina K Lee, Hong Wei Chu, Lan Bai, Liwu Li

Molecular therapy : the journal of the American Society of Gene Therapy 2020 Jan 08

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Tumor-associated immune-suppressive neutrophils are prevalent in various cancers, including colorectal cancer. However, mechanisms of immune-suppressive neutrophils are not well understood. We report that a key innate suppressor, IRAK-M (interleukin-1 receptor-associated kinase M), is critically involved in the establishment of immune-suppressive neutrophils. In contrast to the wild-type (WT) neutrophils exhibiting immune-suppressive signatures of CD11bhighPD-L1highCD80low, IRAK-M-deficient neutrophils are rewired with reduced levels of inhibitory molecules PD-L1 and CD11b, as well as enhanced expression of stimulatory molecules CD80 and CD40. The reprogramming of IRAK-M-deficient neutrophils is mediated by reduced activation of STAT1/3 and enhanced activation of STAT5. As a consequence, IRAK-M-deficient neutrophils demonstrate enhanced capability to promote, instead of suppress, the proliferation and activation of effector T cells both in vitro and in vivo. Functionally, we observed that the transfusion of IRAK-M-/- neutrophils can potently render an enhanced anti-tumor immune response in the murine inflammation-induced colorectal cancer model. Collectively, our study defines IRAK-M as an innate suppressor for neutrophil function and reveals IRAK-M as a promising target for rewiring neutrophils in anti-cancer immunotherapy. Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Citation

Yao Zhang, Na Diao, Christina K Lee, Hong Wei Chu, Lan Bai, Liwu Li. Neutrophils Deficient in Innate Suppressor IRAK-M Enhances Anti-tumor Immune Responses. Molecular therapy : the journal of the American Society of Gene Therapy. 2020 Jan 08;28(1):89-99