Tumor cell-macrophage crosstalk promotes immunotherapy resistance via lipid metabolism

Abstract Immune-checkpoint blockade (ICB) therapies have transformed the treatment landscapes of hepatocellular carcinoma (HCC). However, the immunosuppressive tumor microenvironment (TME) constructed by tumor cells restricts the responsiveness of ICB therapies to a minority of patients. Triggering receptor expressed on myeloid cells-2 (TREM2) counteracts inflammation and maintains metabolic fitness in myeloid cells. Single-cell RNA-sequencing analysis of our pembrolizumab study (NCT03419481) identified a subset of tumor-associated macrophages over-expressing TREM2 in non-responders. Consistently, our syngeneic ICB-resistant HCC mouse models verified a group of Trem2+ myeloid cells, which were accumulated in the lipid-rich TME of ICB-resistant tumors. Compared to the parental ICB-sensitive tumor cells, the conditional medium (CM) of ICB-resistant tumor cells significantly increased Trem2 expression in macrophages, which was abolished when lipids in the CM were depleted. Notably, lentivirus-mediated Trem2 ablation reduced lipid accumulation in TME and overcame anti-PD-1 resistance with increased cytotoxic CD8+ T cell infiltration. In conclusion, our study highlights TREM2 as an immuno-metabolic target to enhance HCC immunotherapy. This study is supported by Collaborative Research Fund (C4045-18W) and Li Ka Shing Foundation. Z.L. is supported by Hong Kong PhD Fellowship Scheme.