The complex network of cells and molecules surrounding a tumor, including stromal cells, immune cells, extracellular matrix, and blood vessels, collectively refers to as the tumor microenvironment (TME)1,2. Tumor cells require nutrients such as glucose, amino acids and fatty acid to grow and proliferate3,4. However, due to restricted blood supply and competition from other cells, the TME has always been a nutritionally competitive environment for both tumor cells and immune cells. To overcome these restrictions, tumor cells have evolved various strategies such as altering their metabolic pathways, inducing angiogenesis, and exploiting neighboring cells for nutrients.
T cells are critical for activating the immune system against cancer; however, persistent exposure to cancer antigens and a nutrient-deficient environment can lead to T cell exhaustion 5. Our study reveals that CD4 T cells within the TME exhibit upregulation of the exhaustion marker PD-1. While CD8 T cell exhaustion has been well-established and is a target of immunotherapy for cancer patients6-10, relatively few studies have focused on the significance of PD-1 inhibition and functional recovery of CD4 T cells. Therefore, our study represents a conceptual advance in the field of cancer immunology by highlighting the importance of methionine as a crucial metabolite in the epigenetic regulation of PD-1 expression in CD4 T cells and in overcoming CD4 T cell exhaustion.
Tumor cells utilize methionine from the TME, and a low methionine level in the TME significantly decreases the H3K79me2 level in tumor-infiltrating CD4 T cells, impairing AMPK expression. Reduced AMPK expression in tumor-infiltrating CD4 T cells induces unfolded protein response by increasing the splicing of XBP1, which leads to higher PD-1 expression. We found that extracellular supplementation of methionine limited the expression of PD-1 in tumor-infiltrating CD4 T cells. Additionally, genetic ablation of SLC43A2, a major methionine transporter, in B16F10 melanoma cells resulted in reduced tumor growth by decreasing PD-1 expression in tumor-infiltrating CD4 T cells.
In summary, our study demonstrates that cancer cells consuming methionine results in a deficiency of methionine in the TME. This leads to a gradual increase in PD-1 expression in CD4 T cells, causing exhaustion of CD4 T cells and impaired anti-tumor immunity. Therefore, it is crucial to maintain an adequate level of methionine in the TME to restore H3K79 methylation. H3K79me2 on the Prkaa1 promoter site promotes the expression of AMPK that regulate PD-1 expression, ultimately improving anti-tumor immunity by CD4 T cells.
Additionally, the role of other essential amino acids in regulating anti-tumor immunity beyond PD-1 expression requires further investigation.
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2 Henke, E., Nandigama, R. & Ergün, S. Extracellular matrix in the tumor microenvironment and its impact on cancer therapy. Frontiers in molecular biosciences 6, 160 (2020).
3 Pavlova, N. N. & Thompson, C. B. The emerging hallmarks of cancer metabolism. Cell metabolism 23, 27-47 (2016).
4 Papalazarou, V. & Maddocks, O. D. Supply and demand: Cellular nutrient uptake and exchange in cancer. Molecular Cell 81, 3731-3748 (2021).
5 Pauken, K. E. & Wherry, E. J. Overcoming T cell exhaustion in infection and cancer. Trends in immunology 36, 265-276 (2015).
6 Dolina, J. S., Van Braeckel-Budimir, N., Thomas, G. D. & Salek-Ardakani, S. CD8+ T cell exhaustion in cancer. Frontiers in immunology 12, 715234 (2021).
7 Sen, D. R. et al. The epigenetic landscape of T cell exhaustion. Science 354, 1165-1169 (2016).
8 McLane, L. M., Abdel-Hakeem, M. S. & Wherry, E. J. CD8 T cell exhaustion during chronic viral infection and cancer. Annual review of immunology 37, 457-495 (2019).
9 Haymaker, C., Wu, R. C., Bernatchez, C. & Radvanyi, L. G. PD-1 and BTLA and CD8+ T-cell “exhaustion” in cancer: “Exercising” an alternative viewpoint. Oncoimmunology 1, 735-738 (2012).
10 Bian, Y. et al. Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. Nature 585, 277-282 (2020).
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