Scavenger Receptor CD36 Regulates Inflammatory and Type-I Interferon Responses in Tumor-Associated Macrophages

Abstract

Abstract Macrophages are plastic cells of innate immune system with diverse functions in tissue homeostasis. Despite their abundance in the tumor microenvironment (TME), the functions of tumor-associated macrophages (TAMs) and their regulation mechanisms remain largely unknown. Macrophages are also key players in metabolic processes including lipid metabolism. As TME has been known as a “lipid-rich” environment, we are interested in understanding how TAMs’ metabolism and function are regulated by lipid receptors. In this research, we firstly characterized the lipid metabolic phenotype of TAMs in mouse tumor models. We found the tolerogenic subset of TAM (high expression of F4/80 and PD-L1) is lipid-laden and has greater ability to import lipids. We found F4/80 hiTAMs highly express scavenger receptor CD36 which binds to oxidized low-density lipoprotein (oxLDL) in TME. Using myeloid-specific knockout (Cd36flox/floxx Csf1r-Cre) mouse models, we observed that CD36-deficient TAMs lost binding to oxLDL, down-regulated expression of immunosuppressive molecules PD-L1 and CD206, while up-regulated secretion of inflammatory cytokines (TNF, IL-12, IL-1b) and IFNb. Overall, this reprogrammed TAM functional state leads to better anti-tumor immunity. Mechanistically, we conducted single-cell RNA-sequencing and found inflammatory response and type-I interferon response pathways were up-regulated in CD36-deficient TAMs. Furthermore, we showed that IFNb and P38 play critical roles in CD36-dependent immune regulations. In summary, our data suggests that scavenger receptor CD36 plays critical roles in functional reprogramming of TAMs; and blocking CD36 may have multi-faceted beneficial effects for future cancer immunotherapies. Supported by fellowship from American Heart Association