MacroH2A restricts melanoma progression via inhibition of chemokine expression in cancer-associated fibroblasts [scRNA-seq]. MacroH2A restricts melanoma progression via inhibition of chemokine expression in cancer-associated fibroblasts [scRNA-seq]

The histone variant macroH2A has been implicated as a tumor suppressor in melanoma and other cancers, yet its role in the tumor microenvironment remains unappreciated. Here we show that mice constitutively lacking macroH2A variants exhibit increased melanoma tumor burden compared to their wild-type counterparts, which is associated with an altered intratumoral immune cell compartment. MacroH2A-deficient tumors display an accumulation of immunosuppressive monocytes and decreased functional cytotoxic T cells. Consistent with this compromised anti-tumor response, macroH2A-deficient tumors displayed upregulation of chemokines such as Ccl2, Cxcl1 and Il6. Through single cell transcriptomics of the entire melanoma microenvironment, we identified the source of these pro-tumor myeloid chemoattractants as cancer-associated fibroblasts, whose frequency and activation were increased in the absence of macroH2A. Chemokine gene expression was hyper-inducible in the absence of macroH2A and accompanied by an altered epigenetic landscape. In sum, we uncovered a tumor suppressive role for macroH2A through repression of chemokine induction in the tumor stroma. Overall design: Single cell profiling of gene expression was carried out in WT and macroH2A deficient melanomas was carried out to identify cell types involved in increased tumor growth and chemokine overexpression in the absence of macroH2A.

组蛋白变体macroH2A（macroH2A）已被证实为黑色素瘤及其他癌症的抑癌因子，但其在肿瘤微环境中的作用却长期未受重视。本研究发现，组成型缺失macroH2A变体的小鼠，其黑色素瘤负荷较野生型对照小鼠显著升高，这与肿瘤内免疫细胞组分的改变密切相关。macroH2A缺陷型肿瘤中，免疫抑制性单核细胞发生蓄积，而功能性细胞毒性T细胞则减少。与这一受损的抗肿瘤免疫应答相一致，macroH2A缺陷型肿瘤中Ccl2、Cxcl1及Il6等趋化因子的表达均出现上调。通过对整个黑色素瘤微环境开展单细胞转录组测序（single cell transcriptomics），我们明确了这些促肿瘤髓系趋化因子的来源为癌症相关成纤维细胞（cancer-associated fibroblasts）；在macroH2A缺失的情况下，这类细胞的丰度与活化水平均有所升高。在缺失macroH2A的状态下，趋化因子基因的表达呈现超诱导特性，并伴随表观遗传景观的改变。综上，本研究揭示了macroH2A通过抑制肿瘤间质中趋化因子的诱导表达，从而发挥抑癌作用。实验设计：本研究对野生型（WT，wild-type）与macroH2A缺陷型黑色素瘤开展基因表达单细胞谱分析，以明确在macroH2A缺失时，参与肿瘤生长加速与趋化因子过度表达的细胞类型。