Chitinase 3-like-1 (CHI3L1) Inhibits Innate Anti-Tumor and Tissue Remodeling Immune Responses by Regulating CD47-SIRPα and CD24-Siglec10-Mediated Phagocytosis

Innate immune responses such as phagocytosis are critically linked to the generation of adaptive immune responses against the neoantigens in cancer and the efferocytosis that is essential for homeostasis in diseases characterized by lung injury, inflammation, and remodeling as in Chronic Obstructive Pulmonary Disease (COPD). Chitinase 3-like-1 (CHI3L1) is induced in many cancers where it inhibits adaptive immune responses by stimulating immune checkpoint molecules (ICPs) and portends a poor prognosis. CHI3L1 is also induced in COPD where it regulates epithelial cell death. Here we demonstrate that pulmonary melanoma metastasis inhibits macrophage phagocytosis by stimulating the CD47-SIRPα and CD24-Siglec10 phagocytosis checkpoint pathways while inhibiting macrophage eat me signals from calreticulin and HMGB1. We also demonstrate that these effects on macrophage phagocytosis are mediated by CHI3L1 stimulation of the SHP-1 and SHP-2 phosphatases and the inhibition of the accumulation and phosphorylation of cytoskeleton-regulating non-muscle myosin IIa. This inhibition of innate immune responses like phagocytosis provides a mechanistic explanation for the ability of CHI3L1 to stimulate ICPs and inhibit adaptive immune responses in cancer and diseases like COPD. The ability of CHI3L1 to simultaneously inhibit innate immune responses, stimulate ICPs, inhibit T cell co-stimulation, and regulate a number of other oncogenic and inflammation pathways suggest that CHI3L1-targeted therapeutics are promising interventions in cancer, COPD and other disorders. ### Competing Interest Statement JAE is a cofounder of Elkurt Therapeutics and is a founder of and stockholder of and serves on the Scientific Advisory Board for Ocean Biomedical, Inc., which develops inhibitors of 18 glycosyl hydrolases as therapeutics. CGL, CML, BM, and SK serves on consultants for Ocean Biomedical. Inc. JAE, CGL and SK have composition of matter and use patents relating to antibodies against CHI3L1. The other Brown University authors have declared that no conflict of interest exists. A.M.K.C. is a cofounder and consultant, and equity stockholder for Proterris, which develops therapeutic uses for carbon monoxide. A.M.K.C. is a consultant and equity stockholder for SPEXIS. A.M.K.C is a member for Medforth Board of Directors. A.M.K.C. has a use patent on CO and has a patent in COPD. DLD has received grant support from Bayer and has received awards from the Alpha-1 Foundation and the Doris Duke Foundation. EKS has received grant support from Bayer and Northpond Laboratories.