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