Deletion of MyD88 in T-cells Improves Anti-Tumor Activity in Melanoma

Am J Pathol. 2024 Mar 3:S0002-9440(24)00083-X. doi: 10.1016/j.ajpath.2024.02.012. Online ahead of print.ABSTRACTCytotoxic CD8+ T-cells are central to the anti-tumor immune response by releasing cytotoxic granules that kill tumor cells. They are activated by antigen presenting cells, which become activated by DAMPs (damage associated molecular patterns) through MyD88 (myeloid differentiation response 88). However, the suppressive tumor microenvironment promotes T-cell tolerance to tumor antigens in part by enhancing the activity of immune checkpoint molecules that prevent CD8+ T-cell activation and cytotoxicity. We recently reported that MyD88 limits CD4+ T-cell activation during cardiac adaptation to stress and hypothesized that a similar mechanism exists in CD8+ T-cells which could be modulated to improve anti-tumor immunity. We found that adoptive transfer of MyD88-/- CD8+ T-cells in melanoma-bearing T-cell deficient mice resulted in slower tumor growth, greater intratumoral T-cell accumulation, and higher melanoma cell death compared to transfer of WT CD8+ T-cells. These findings were also observed in T-cell specific MyD88-/- mice compared to WT littermates implanted with melanoma. Mechanistically, we found that deletion of MyD88 enhances CD8+ T-cell activation and survival, and TCR induced degranulation of cytotoxic molecules, overall improving their killing of melanoma cells. This enhanced cytotoxicity was retained in mice bearing tumors expressing the specific antigen f...
Source: The American Journal of Pathology - Category: Pathology Authors: Source Type: research