Fig. 3: Tumor mtDNA mutations reshape the immune microenvironment.
a, Survival of C57/BL6 mice subcutaneously injected with indicated cells (n = 14, 12, 7, 12 and 8 animals). b, Mean tumor weight at endpoint (n = 14, 12, 7, 12 and 8 individual tumors). Error bars, s.d. c, GSEA of bulk tumor RNA-seq data (n = 5–6 individual tumors per genotype). Only gene sets with Padj < 0.1 are shown. TNFα, tumor necrosis factor alpha. d, GSEA of RNA-seq obtained from HMF database of patients with metastatic melanoma. Cancers are stratified by mtDNA status into wild type and mtDNA mutant with >50% VAF. e, UMAP of Seurat clustered whole tumor scRNA-seq from indicated samples. f, UMAP indicating cell type IDs. DC, dendritic cells; pDC, plasmacytoid dendritic cell; NK, natural killer. g, GSEA of malignant cells identified in scRNA-seq analysis. Comparison is wild-type tumors versus all mutant tumors. h–l, UMAPs colored by GSEA score for IFNα response (h), IFNγ response (i), IL2-Stat5 signaling (j), inflammatory response (k) and oxidative phosphorylation (l). m, Proportion of tumor-resident S100a9+ neutrophils relative to total malignant and non-malignant cells (n = 7, 6 and 3 individual tumors). Boxplots indicate mean and interquartile range; error bars, s.e.m. One-way ANOVA test with Sidak multiple comparisons test (b), two-tailed Wilcoxon signed rank test (c,d,g–l) and two-tailed Student’s t-test (m) were applied. Number of replicates are described across conditions from left to right as presented.
