IRF8 Governs Tumor-Associated Macrophage Control of T Cell Exhaustion
Nixon, B.; Kuo, F.; Liu, M.; Capistrano, K.; Do, M.; Franklin, R.; Wu, X.; Kansler, E.; Srivastava, R.; Purohit, T.; Sanchez, A.; Vuong, L.; Krishna, C.; Morse, H.; Hsieh, J.; Chan, T.; Murphy, K.; Moon, J.; Hakimi, A.; Li, M.
Show abstract
Tumor progression is associated with overstimulation of cytotoxic T lymphocytes (CTLs), resulting in a dysfunctional state of exhaustion. How T cell exhaustion is elicited in the tumor remains poorly understood. Here we show that tumor-associated macrophages (TAMs) present cancer cell antigen and induce CTL exhaustion through a gene expression program dependent on the transcription factor interferon regulatory factor-8 (IRF8). In a transgenic model of murine breast cancer, CTL priming was supported by IRF8-dependent dendritic cells; yet, CTL exhaustion required TAM expression of IRF8, and its ablation suppressed tumor growth. An analysis of the highly immune-infiltrated human renal cell carcinoma tumors revealed abundant TAMs that expressed IRF8 and were enriched for an IRF8 gene expression signature. The IRF8 signature co-segregated with T cell exhaustion markers and was negatively associated with long-term patient survival. Thus, CTL exhaustion is promoted by TAMs via IRF8, and this crosstalk may be disrupted in TAM-targeted therapies.
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