Abstract A016: Reprogramming of immune-enhancing neutrophils by subclinical low-dose endotoxin for the treatment of cancer

Abstract

Abstract Despite the recent resurgence of the pioneering concept of “Coley’s toxin” in ushering in anti-cancer immune therapies highlight by check-point inhibitors and CAR-T approaches, fundamental mechanisms responsible for the immune-enhancing efficacy of innate low-dose “Coley’s toxin” remain poorly understood. This study aims to reveal the novel reprogramming of immune-enhancing neutrophils by super-low dose endotoxin conducive for innate immunity-based anti-cancer therapies. We perform scRNAseq analyses and reveal that neutrophils trained by super-low dose endotoxin (SL-LPS) adopt a unique immune-enhancing cluster characterized by CD177loCD11BloCD80hiCD40hi. Transfusion of SL-LPS trained neutrophils into recipient mice with AOM/DSS-inducing colorectal tumors exhibit potent efficacy in reducing tumor burden. SL-LPS trained neutrophils show relieved suppression of adaptive T cells as compared to un-trained neutrophils in vivo and in vitro. Mechanistically, SL-LPS enables the generation of immune-enhancing neutrophils through activating STAT5 and reducing innate suppressor IRAK-M. Herein, we present evidence revealing the key principle that underlying the immune-enhancing effects of super-low dose endotoxin, unrevealing the long-held mystery of low-dose “Coley’s toxin” in generically boosting host anti-tumor defense. Our mechanistic and translational observations not only reveal fundamental mechanisms for re-programming immune-enhancing neutrophils, but also provide a proof-of-principle in developing innate neutrophil-based anti-tumor therapeutics. Citation Format: Yao Zhang, Liwu Li. Reprogramming of immune-enhancing neutrophils by subclinical low-dose endotoxin for the treatment of cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A016.