Tumorous niche drives NK exhaustion by disordering metabolic program

Abstract

Abstract Natural killer (NK) cells are important effectors of the immune system that can lyse malignancy-transformed cells. In the human liver, NK cells can account up to 50% of the total lymphocyte population. How NK cells lose immune surveillance occurs in hepatocellular carcinoma progression. In this study, 75 cases from hepatocellular carcinoma (HCC) patients were analyzed by RNA sequence, pathology, flow cytometry and cell culture in vitro. We found a significant enrichment of infiltrating T cells within the tumor tissues of HCC patients but not NK cells, as compared to the adjacent peritumoral tissues. It is interesting that the infiltrating NK cells enrich CD56brightCD49a+ NK subset, like liver-resident NK. Nearly 50% of the entire healthy liver NK cell population is composed of functionally relevant CD56bright CD49a-NK cells, and almost all of the subset was lose. The infiltrating CD56brightCD49a+ NK cells present exhausted phenotype and downregulated expression of efficacy molecules of CD11b, CD226 and IFN-γ. We also found a few of CD56dimCD16+ NK cells were infiltrating, which were similar to their peripheral circulating counterparts in transcription and phenotype, but the lower effect function and viability of infiltrating NK cells compared with normal liver or peripheral circulating counterparts. Dynamic reprogramming of metabolism is essential for immune cell stable liveness and effector function. Gene Ontology profiling and metabolism analysis revealed the infiltrating NK cells bioenergetic insufficiencies and enrichment of metabolic oxygen specis leading to its subset variations and immune surveillance insensitivity.