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. 2022 Aug 10;12:969563. doi: 10.3389/fonc.2022.969563

Figure 2.

Figure 2

Tumor drives T cell exhaustion by manipulating the methionine cycle of T cells. Tumor cells promote T cell dysfunction by outcompeting T cells for methionine and potentially other amino acids. For example, B16F10 Tumor cells induce T cell exhaustion by outcompeting T cells for methionine uptake. This results in decreases in global H3K79me2 expression and the expression of Signal Transducer and Activator of Transcription 5 (STAT5). As a consequence, tumor-infiltrating CD8+ T cells displayed a reduction in the expression of interferon gamma (IFN-γ) and granzyme-B. On the other hand, hepatocellular carcinoma (HCC) tumors may produce immune-suppressive metabolites through methionine metabolism that help to induce T cell exhaustion. Elevated levels of S-adenosylmethionine (SAM) and 5′-methylthioadenosine (MTA) in HCC tumors are closely associated with T cell exhaustion. This may be explained by the immunosuppressive function of SAM and MTA. When supplemented in vitro, they promote the expression of exhaustion marks, inhibit IFN-γ expression, and cause a closed chromatin structure in human CD8+ T cells.