Tumor-associated macrophages expressing the transcription factor IRF8 promote T cell exhaustion in cancer Journal Article
| Authors: | Nixon, B. G.; Kuo, F.; Ji, L.; Liu, M.; Capistrano, K.; Do, M.; Franklin, R. A.; Wu, X.; Kansler, E. R.; Srivastava, R. M.; Purohit, T. A.; Sanchez, A.; Vuong, L.; Krishna, C.; Wang, X.; Morse, H. C. 3rd; Hsieh, J. J.; Chan, T. A.; Murphy, K. M.; Moon, J. J.; Hakimi, A. A.; Li, M. O. |
| Article Title: | Tumor-associated macrophages expressing the transcription factor IRF8 promote T cell exhaustion in cancer |
| Abstract: | Tumors are populated by antigen-presenting cells (APCs) including macrophage subsets with distinct origins and functions. Here, we examined how cancer impacts mononuclear phagocytic APCs in a murine model of breast cancer. Tumors induced the expansion of monocyte-derived tumor-associated macrophages (TAMs) and the activation of type 1 dendritic cells (DC1s), both of which expressed and required the transcription factor interferon regulatory factor-8 (IRF8). Although DC1s mediated cytotoxic T lymphocyte (CTL) priming in tumor-draining lymph nodes, TAMs promoted CTL exhaustion in the tumor, and IRF8 was required for TAMs’ ability to present cancer cell antigens. TAM-specific IRF8 deletion prevented exhaustion of cancer-cell-reactive CTLs and suppressed tumor growth. Tumors from patients with immune-infiltrated renal cell carcinoma had abundant TAMs that expressed IRF8 and were enriched for an IRF8 gene expression signature. Furthermore, the TAM-IRF8 signature co-segregated with CTL exhaustion signatures across multiple cancer types. Thus, CTL exhaustion is promoted by TAMs via IRF8. © 2022 Elsevier Inc. |
| Keywords: | genetics; mouse; animal; metabolism; animals; mice; dendritic cell; renal cell carcinoma; kidney neoplasms; antigen presentation; dendritic cells; kidney tumor; carcinoma, renal cell; cytotoxic t lymphocyte; t-lymphocytes, cytotoxic; interferon regulatory factors; tumor-associated macrophage; tumor-associated macrophages; antigen-presenting cell; interferon consensus sequence binding protein; interferon regulatory factor; humans; human; t cell exhaustion; irf8 |
| Journal Title: | Immunity |
| Volume: | 55 |
| Issue: | 11 |
| ISSN: | 1074-7613 |
| Publisher: | Cell Press |
| Date Published: | 2022-11-08 |
| Start Page: | 2044 |
| End Page: | 2058.e5 |
| Language: | English |
| DOI: | 10.1016/j.immuni.2022.10.002 |
| PUBMED: | 36288724 |
| PROVIDER: | scopus |
| PMCID: | PMC9649891 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2022 -- Source: Scopus |
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