Nutrition deprivation affects the cytotoxic effect of CD8 T cells in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the third leading cause of cancer-related death worldwide. Factors including carcinogens, infection of hepatitis viruses, alcohol abuse, and metabolic disorders such as non-alcoholic fatty liver disease mainly contribute to HCC initiation and progression. Immunotherapy is one of the most powerful tools for unresectable HCC treatment in patients. CD8⁺ T cells are a major immune component in the tumor microenvironment with cytotoxic effects against cancer cells. However, these CD8⁺ T cells commonly display an exhaustion phenotype with high expression of programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing-3, and/or lymphocyte-activation gene 3, producing low levels of perforin (PRF1) and granzyme B (GZMB), as well as anti-tumor cytokines, such as interferon gamma and tumor necrosis factor alpha. In the referenced study, the authors also showed that deprivation of glutamine decreased the antitumor function of CD8⁺ T cells, as well as the production of PRF1 and GZMB. However, the role of each amino acid in T cell function and exhaustion may depend on tumor type and tumor microenvironment, including the source of other nutrients. Overall, amino acids or other nutrient metabolites in the tumor microenvironment play a pivotal role in both tumor growth and immune response.