Hepatocellular carcinoma cells induce γδ T cells through metabolic reprogramming into tumor-progressive subpopulation

Abstract

Tumor immune microenvironment (TIME) is a tiny structure that contains multiple immune cell components around tumor cells, which plays an important role in tumorigenesis, and is also the potential core area of activated immunotherapy. How immune cells with tumor-killing capacity in TIME are hijacked by tumor cells during the progression of tumorigenesis and transformed into subpopulations that facilitate cancer advancement is a question that needs to be urgently addressed nowadays. γδ T cells (their T cell receptors are composed of γ and δ chains), a unique T cell subpopulation distinguished from conventional αβ T cells, are involved in a variety of immune response processes through direct tumor-killing effects and/or indirectly influencing the activity of other immune cells. However, the presence of γδ T cells in the tumor microenvironment (TME) has been reported to be associated with poor prognosis in some tumors, suggesting that certain γδ T cell subsets may also have pro-tumorigenic effects. Recent studies have revealed that metabolic pathways such as activation of glycolysis, increase of lipid metabolism, enhancement of mitochondrial biosynthesis, alterations of fatty acid metabolism reshape the local TME, and immune cells trigger metabolic adaptation through metabolic reprogramming to meet their own needs and play the role of anti-tumor or immunosuppression. Combining previous studies and our bioinformatics results, we hypothesize that γδT cells compete for resources with hepatocellular carcinoma (HCC) cells by means of fatty acid metabolic regulation in the TME, which results in the weakening or loss of their ability to recognize and kill HCC cells through genetic and epigenetic alterations, thus allowing γδT cells to be hijacked by HCC cells as a subpopulation that promotes HCC progression.

Keywords: fatty acid; hepatocellular carcinoma; metabolic reprogramming; tumor immune microenvironment; γδT cells.

Figure 1

Potential biological mechanisms of HCC infiltrating γδT cells-related differentially expressed genes (DEGs). (A) Volcano map of DEGs, (B) heatmap of DEGs, and (C) the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses for high and low γδT cells-related DEGs based on the TCGA dataset.

Figure 2

Metabolic regulation and feedback of γδT cell in tumor microenvironment. γδT cell activation and signaling through T cell receptor (TCR) activates PI3K/Akt/mTOR and cMyc pathways, leading to increased glycolysis and metabolism, decreased fatty acid oxidation, without obvious changes in oxidative phosphorylation levels. With the extremely rapid expansion of cancer cells, T cells undergo metabolic reprogramming in order to survive by means of fatty acid metabolism, resulting in altered molecular phenotypes (e.g., PD1, CTLA4), thus becoming a subpopulation of tumor-promoting progression T cells.

Figure 3

Immune cells trigger metabolic adaptation through metabolic reprogramming in tumor microenvironment. The conditions of tumor microenvironment (TME), including nutrient competition, low pH, limited oxygen, and accumulation of metabolites, result in immunosuppressive or tolerogenic phenotypes of immune cells and encourage metabolism that relies more on oxidative phosphorylation and fatty acid oxidation to fulfill energy needs. These conditions also promote differentiation and accumulation of Treg, M2-like macrophages, and MDSCs, which drives an immunosuppressive microenvironment generally. MDSCs, myeloid-derived dendritic cells; TAN, tumor-associated neutrophils.