The tumor microenvironment is the primary arena in which tumor cells and the host immune system interact. Characterization of the nature of immune responses in the human cancer microenvironment holds the key to understanding tumor immunity and designing and improving current cancer immunotherapy 1,2. Our research team investigates the human cancer microenvironment with the goal of understanding genetic, epigenetic, and metabolic nature of human tumor immune responses and developing mechanism-informed combination therapies for cancer. Our work includes the first demonstration of the expression and functional blockade of PD-L1 (B7-H1) in the human cancer microenvironment and human tumor draining lymph nodes 3. This early work points towards the involvement of the PD-L1 pathway in T cell dysfunctionality in the human cancer microenvironment 1,3,4. Subsequently, based on murine model with chronic viral infection, T cell dysfunctionality has been integrated into the concept of “T cell exhaustion” 5. Much effort has been devoted to identifying the molecular basis of tumor infiltrating T cell dysfunction (exhaustion). Recent studies have indicated that TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion 6-8. As the nutrient competition occurs between tumor cells and non-tumor cells (such as T cells) in the tumor micro-environment, we have reasoned that tumor infiltrating T cell exhaustion may be directly linked to abnormal metabolism in the tumor microenvironment. In our study, we found tumor cells are addicted to methionine through high expression of SLC43A2, a major methionine transporter. Mechanistically, the disrupted methionine metabolism in T cells decreases intracellular methionine and the methyl donor S-adenosylmethionine (SAM), resulting in loss of H3K79me2, an active transcriptional histone mark. Consequently, loss of DOT1L-mediated H3K79me2 directly leads to reduced STAT5 expression and impaired T cell-mediated anti-tumor immunity. Our work demonstrates a long-awaited mechanistic connection between metabolism, histone pattern, and functional profile in tumor infiltrating T cells. On this basis, selectively targeting tumor methionine metabolism may be a novel approach for cancer immunotherapy.
Here is the link to the paper: https://doi.org/10.1038/s41586-020-2682-1
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