FASN inhibition complements PD-L1 checkpoint blockade by suppressing palmitoylation of MHC-I in hepatocellular carcinoma

Abstract

The advent of immune checkpoint inhibitors (ICIs) has revolutionized the treatment approach for hepatocellular carcinoma (HCC). However, patients with lowered major histocompatibility complex class I (MHC-I) expression continue to exhibit resistance to ICIs, and there are limited targets available for enhancing MHC-I levels. In this study, we discovered that inhibiting fatty acid synthase (FASN), either genetically or pharmacologically, elevated HCC cells' MHC-I levels. The cytotoxicity of CD8+ T lymphocytes that are specific to the antigens was activated and antigen presentation was strengthened by this increase in MHC-I. Mechanistically, FASN inhibition decreased MHC-I's palmitoylation, which in turn inhibited lysosome degradation of MHC-I. We identified the palmitoyltransferase DHHC3 as a direct binder of MHC-I, exerting a negative regulation on the levels of MHC-I protein. The lack of Fasn increased MHC-I levels in an orthotopic HCC mice model and facilitate CD8+ T lymphocytes infiltrating the tumor and eliminating cancer cells. Moreover, combining anti-PD-L1 antibody with two different FASN inhibitors, orlistat and TVB-2640, effectively inhibited the growth of tumors in vivo. Furthermore, it was shown that a higher percentage of cytotoxic CD8+ T cells was connected with decreased expression of FASN by multiplex immunohistochemistry of human HCC samples and bioinformatic analysis of TCGA data. The discovery of FASN as a negative regulator of MHC-I offers a rationale for combining FASN inhibitors with immunotherapy for the treatment of HCC.