Programs, origins and immunomodulatory functions of myeloid cells in glioma

• 成果类型: Article
• 署名作者: Miller, Tyler E.; El Farran, Chadi A.; Couturier, Charles P.; Chen, Zeyu; D'Antonio, Joshua P.; Verga, Julia; Villanueva, Martin A.; Castro, L. Nicolas Gonzalez; Tong, Yuzhou Evelyn; Saadi, Tariq Al; Chiocca, Andrew N.; Zhang, Yuanyuan; Fischer, David S.; Heiland, Dieter Henrik; Guerriero, Jennifer L.; Petrecca, Kevin; Suva, Mario L.; Shalek, Alex K.; Bernstein, Bradley E.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Ragon Institute; Harvard University; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; McGill University; University of Freiburg; Northwestern University; Feinberg School of Medicine; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; University System of Ohio; Case Western Reserve University; University System of Ohio; Case Western Reserve University; McGill University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2006
• DOI: 10.1038/s41586-025-08633-8
• 发表日期: 2025-04-24
• 关键词: single-cell; analysis reveals; web server; macrophages; inhibition; microglia; protein; STATES; tumors

摘要

Gliomas are incurable malignancies notable for having an immunosuppressive microenvironment with abundant myeloid cells, the immunomodulatory phenotypes of which remain poorly defined1. Here we systematically investigate these phenotypes by integrating single-cell RNA sequencing, chromatin accessibility, spatial transcriptomics and glioma organoid explant systems. We discovered four immunomodulatory expression programs: microglial inflammatory and scavenger immunosuppressive programs, which are both unique to primary brain tumours, and systemic inflammatory and complement immunosuppressive programs, which are also expressed by non-brain tumours. The programs are not contingent on myeloid cell type, developmental origin or tumour mutational state, but instead are driven by microenvironmental cues, including tumour hypoxia, interleukin-1 beta, TGF beta and standard-of-care dexamethasone treatment. Their relative expression can predict immunotherapy response and overall survival. By associating the respective programs with mediating genomic elements, transcription factors and signalling pathways, we uncover strategies for manipulating myeloid-cell phenotypes. Our study provides a framework to understand immunomodulation by myeloid cells in glioma and a foundation for the development of more-effective immunotherapies.