Cancer SLC43A2 alters T cell methionine metabolism and histone methylation

Yingjie Bian, Wei Li, and Weiping Zou

Like Comment
Read the paper

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:

1. Zou, W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nature Reviews Cancer 5, 263-274, doi:10.1038/nrc1586 (2005).
2. Zou, W., Wolchok, J. D. & Chen, L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Science Translational Medicine 8, 328rv324, doi:10.1126/scitranslmed.aad7118 (2016).
3. Curiel, T. J. et al. Blockade of B7-H1 improves myeloid dendritic cell–mediated antitumor immunity. Nature Medicine 9, 562-567, doi:10.1038/nm863 (2003).
4. Zou, W. & Chen, L. Inhibitory B7-family molecules in the tumour microenvironment. Nature Reviews Immunology 8, 467-477, doi:10.1038/nri2326 (2008).
5. Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682-687, doi:10.1038/nature04444 (2006).
6. Khan, O. et al. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 571, 211-218, doi:10.1038/s41586-019-1325-x (2019).
7. Alfei, F. et al. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 571, 265-269, doi:10.1038/s41586-019-1326-9 (2019).
8. Yao, C. et al. Single-cell RNA-seq reveals TOX as a key regulator of CD8+ T cell persistence in chronic infection. Nature Immunology 20, 890-901, doi:10.1038/s41590-019-0403-4 (2019).

Yingjie Bian

Postdoc, University of Michigan

No comments yet.