MacroH2A represses melanoma growth by modulating chromatin architecture and inflammation in the stroma.

  • Major Finding: MacroH2A represses melanoma growth by modulating chromatin architecture and inflammation in the stroma.

  • Concept: Chromatin looping changes underlie inflammatory gene expression in macroH2A-deficient cancer-associated fibroblasts.

  • Impact: The tumor-suppressive effects of macroH2A have potential implications for immunotherapy response in melanoma.

MacroH2A has tumor-suppressive functions in many cancers, including advanced melanoma, but its role in the epigenetic regulation of the tumor microenvironment (TME) and how this alters melanoma tumorigenesis in vivo is poorly understood. To investigate the consequences of macroH2A deficiency on the TME and BRAFV600E/PTEN-deficient melanomas, Filipescu and colleagues utilized an autochthonous, immunocompetent mouse model of melanoma and showed that, following melanoma initiation, mice lacking macroH2A harbored increased tumor burden, indicating that macroH2A is a tumor suppressor in melanoma in vivo. Transcriptomic profiling of tumors deficient in macroH2A revealed increased expression of proinflammatory cytokines along with decreased expression of activated CD8+ T-cell markers, while immunophenotyping identified an expansion of monocytes and a decrease in the abundance and activation of CD8+ T cells within the TME. Moreover, single-cell RNA sequencing combined with spatial transcriptomics demonstrated that macroH2A depletion significantly altered differentiation states and cell type composition in melanoma. First, macroH2A depletion promoted melanocyte dedifferentiation toward a proliferative neural crest–like cell state, which is associated with poor prognosis in patients. Second, cancer-associated fibroblasts (CAF) appeared to be the source of increased inflammatory gene expression in macroH2A-deficient tumors, which was also confirmed upon CAF stimulation in culture. Additionally, these CAFs were found to recruit immunosuppressive myeloid cells to the TME. Profiling of chromatin modifications, including active histone marks, within wild-type and macroH2A-deleted CAFs uncovered changes in H3K27ac levels at enhancer elements in contact with promoters of differentially expressed inflammatory genes. Furthermore, macroH2A-deficient CAFs displayed alterations in chromatin architecture and rewired chromatin looping, with increased enhancer–promoter looping occurring near several key upregulated inflammatory signaling genes. In summary, the results of this study show that the tumor-suppressive effects of macroH2A are, in part, mediated by limiting the proinflammatory properties of the tumor stroma through chromatin architecture and suggest that macroH2A expression in tumors could potentially be used to stratify patients and predict immunotherapy response in melanoma.

Filipescu D, Carcamo S, Agarwal A, Tung N, Humblin É, Goldberg MS, et al. MacroH2A restricts inflammatory gene expression in melanoma cancer-associated fibroblasts by coordinating chromatin looping. Nat Cell Biol 2023;25:1332–45.

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