Although clonal neo-antigen burden is associated with improved response to immune therapy, the functional basis for this remains unclear.,Here we study this question in a novel controlled mouse melanoma model that enables us to explore the effects of intra-tumor heterogeneity (ITH) on tumor aggressiveness and immunity independent of tumor mutational burden.,Induction of UVB-derived mutations yields highly aggressive tumors with decreased anti-tumor activity.,However, single-cell-derived tumors with reduced ITH are swiftly rejected.,Their rejection is accompanied by increased T cell reactivity and a less suppressive microenvironment.,Using phylogenetic analyses and mixing experiments of single-cell clones, we dissect two characteristics of ITH: the number of clones forming the tumor and their clonal diversity.,Our analysis of melanoma patient tumor data recapitulates our results in terms of overall survival and response to immune checkpoint therapy.,These findings highlight the importance of clonal mutations in robust immune surveillance and the need to quantify patient ITH to determine the response to checkpoint blockade.,•Novel mouse system to uncouple tumor mutational load and tumor heterogeneity•Lower tumor heterogeneity leads to decreased tumor growth because of immune rejection•Both clone numbers and their genetic diversity mediate tumor growth and rejection•Tumor heterogeneity is linked to patient survival and checkpoint blockade response,Novel mouse system to uncouple tumor mutational load and tumor heterogeneity,Lower tumor heterogeneity leads to decreased tumor growth because of immune rejection,Both clone numbers and their genetic diversity mediate tumor growth and rejection,Tumor heterogeneity is linked to patient survival and checkpoint blockade response,Syngeneic mouse models of melanoma and human patient data are used to explore the effect of intra-tumor heterogeneity on immune response and demonstrate that heterogeneity predicts immunotherapy outcomes better than mutational burden.
Malignant melanoma is a neoplasm of melanocytes, and the microphthalmia‐associated transcription factor (MITF) is essential for the existence of melanocytes.,MITF's relevance for this cell lineage is maintained in melanoma, where it is an important regulator of survival and balances melanoma cell proliferation with terminal differentiation (pigmentation).,The MITF gene is amplified in ~20% of melanomas and MITF mutation can predispose to melanoma development.,Furthermore, the regulation of MITF expression and function is strongly linked to the BRAF/MEK/ERK/MAP‐kinase (MAPK) pathway, which is deregulated in >90% of melanomas and central target of current therapies.,MITF expression in melanoma is heterogeneous, and recent findings highlight the relevance of this heterogeneity for the response of melanoma to MAPK pathway targeting drugs, as well as for MITF's role in melanoma progression.,This review aims to provide an updated overview on the regulation of MITF function and plasticity in melanoma with a focus on its link to MAPK signaling.