Bin Zheng, PhD, an investigator in the Department of Dermatology, is the Senior author of a recent letter published in Nature Metabolism, Myeloid-derived Itaconate Suppresses Cytotoxic CD8+ T Cells and Promotes Tumour Growth.
What were you investigating with this study?
We explore how myeloid-derived suppressor cells (MDSCs), a major group of immunosuppressive cells in the tumor microenvironment, suppress T cells.
What was your approach?
We use cultured immune cells, tumor mouse models and melanoma patient samples.
What did you find?
We found that MDSCs secrete a metabolite called itaconate to suppress T cells and promote tumor growth in mice. Blocking itaconate production enhances the efficacy of immune checkpoint blockade in mice. We also found that lower IRG1 expression is potentially associated with a better response to PD-1 immune checkpoint blockade in patients with melanoma.
What are the implications?
Our findings strongly suggest that IRG1, the enzyme that makes itaconate, is a promising target for immuno-oncology.
Small molecule inhibitors of IRG1 could have the potential to enhance anti-tumor immunity, either as a single agent or in combination with other cancer immunotherapies.
We have shown that IRG1 is selectively expressed in MDSCs—and not in tumor cells or T cells—suggesting this approach could provide a highly favorable therapeutic window with few adverse effects.
What are the next steps?
Our description of itaconate as a novel mediator of the immune-suppressive effects of MDSCs against CD8+ T cells raises several critical questions.
For example, the regulation of IRG1 expression in MDSCs and its induction by tumor cells is unclear.
Further, the direct cellular targets of itaconate in T cells and the specific transporters of itaconate have yet to be revealed.
Given the involvement of MDSCs in the pathogenesis of various infectious diseases, obesity, and aging, it is very likely that this future research will have impacts beyond immune oncology.
Paper Cited: Zhao, H., Teng, D., Yang, L., Xu, X., Chen, J., Jiang, T., Feng, A. Y., Zhang, Y., Frederick, D. T., Gu, L., Cai, L., Asara, J. M., Pasca di Magliano, M., Boland, G. M., Flaherty, K. T., Swanson, K. D., Liu, D., Rabinowitz, J. D., & Zheng, B. (2022). Myeloid-derived itaconate suppresses cytotoxic CD8+ T cells and promotes tumour growth. Nature metabolism, 10.1038/s42255-022-00676-9. Advance online publication. https://doi.org/10.1038/s42255-022-00676-9
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