Neutrophils deficient in innate suppressor IRAK-M enhances anti-tumor immune responses

Abstract

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 CD11b high PD-L1 high CD80 low , 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. Zhang and Diao et al. demonstrated that IRAK-M is important for the establishment of immune-suppressive neutrophils. They found that IRAK-M-deficient neutrophils can be reprogrammed into an immune-enhanced state promoting T cell activation. They also found that the injection of IRAK-M-deficient neutrophils can be effectively used to treat colon cancer.