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

Abstract

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.

Identification of prognostic nutritional index as a reliable prognostic indicator for advanced lung cancer patients receiving immune checkpoint inhibitors

“…A recent report suggested the nutritional status may be correlated with the proportion and function of immune cells (such as T and memory cells) in the tumor microenvironment, therefore affecting the clinical efficacy of the immunotherapies (40). In hepatocellular carcinoma, nutrition deprivation impaired the anti-cancer function of tumor-infiltrating CD8+T cells, partly explaining why low PNI was correlated with reduced ICI efficacy (41). On the other hand, it should be noted that the PNI was not correlated with patient prognosis or identified as an independent prognostic indicator in several included studies (16,18,25,28,29).…”

Metabolic plasticity of T cell fate decision

“…For instance, the glutamine restriction in CD8 + T cells, due to its competition with tumor cells, leads to increase in the expression of PD-1 and LAG-3, thereby, fostering the progression of exhaustion. [22,108,109] Glutamine enters the cell through the transport receptors, SLC1A5 and SLC7A5, and is converted into α-KG for entry into the TCA cycle, thereby orchestrating cellular metabolic and epigenetic landscapes. The metabolic and epigenetic reprogramming resulting from glutamine scarcity likely underlies the mechanisms driving T cell exhaustion and dysfunction within the TME.…”

The Influence of Diet and Its Components on the Development and Prevention of Hepatocellular Carcinoma (HCC)

“…Factors conducive to malnutrition include reduced hunger sensation due to elevated leptin levels, ascites, inflammatory conditions, increased catabolism, and the need for gluconeogenesis, also utilizing branched-chain amino acids (BCAAs), namely, isoleucine, leucine, and valine, typically used for muscle tissue building [ 25 ]. Notably, nutrients impact immune functions and immunotherapy in HCC [ 27 ]. As highlighted in the review by Zhang C et al, asparagine deficiency disrupts the functioning of CD8 lymphocytes, while its excess enhances their anti-tumor activity [ 27 ].…”

“…Notably, nutrients impact immune functions and immunotherapy in HCC [ 27 ]. As highlighted in the review by Zhang C et al, asparagine deficiency disrupts the functioning of CD8 lymphocytes, while its excess enhances their anti-tumor activity [ 27 ]. Inhibiting glutamine breakdown likely activates this subset of lymphocytes, as well [ 27 ].…”

“…As highlighted in the review by Zhang C et al, asparagine deficiency disrupts the functioning of CD8 lymphocytes, while its excess enhances their anti-tumor activity [ 27 ]. Inhibiting glutamine breakdown likely activates this subset of lymphocytes, as well [ 27 ]. Serine is essential for T lymphocyte proliferation, while creatine contributes to slowing down the proliferation of cancer cells, similar to tryptophan, which enhances the cytotoxicity of the immune system cells [ 28 ].…”