Turning immunologically cold tumors into hot ones by activating hepatoma-intrinsic FADD/NF-κB/CCL5 pathway

Abstract

Abstract Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is a distinct variant of HCC that displayed immunologically hot tumor features with prominent tumor-infiltrating CD8+ T lymphocytes (TILs). Our whole exosome sequencing data pointed out an increased prevalence of chromosome 11q13.3 amplification in LEL-HCC, in which 13/17 genes located in 11q13.3 were upregulated. Among these genes, fas-associated death domain (FADD) displayed a strongest correlation with differentially upregulated immune regulatory genes in HCC with 11q13.3 amplicon. In addition, CD8+ T cells preferred to migrate into tumors with higher FADD expression in vitro and in vivo. Mechanistically, FADD activated nuclear factor-κB (NF-κB) that in turn promoted T cell trafficking chemokine C-C motif chemokine ligand 5 (CCL5) production. Furthermore, Fadd expression was positively correlated with Ccl5 and TIL proportions, leading to increased immune checkpoint blockade (ICB) responsiveness in orthotopic HCC mouse models. As LEL-HCC patients also exhibited a concordant higher expression of FADD and CD8, our findings suggested that activation of FADD may turn cold tumors into hot ones and improve HCC ICB responsiveness. This project is supported by grants from Health and Medical Research Fund (07180556) and General Research Fund 2019/20 (14108219).