In mouse models of melanoma, lower intratumoral heterogeneity (ITH) correlated with lower tumor growth.
Major Finding: In mouse models of melanoma, lower intratumoral heterogeneity (ITH) correlated with lower tumor growth.
Concept: In patient data, high levels of ITH predicted reduced survival and poorer response to immunotherapy.
Impact: This study shows that ITH is an important factor in melanoma and may be a prognostic biomarker.
Recent studies have indicated that intratumoral heterogeneity (ITH) may be an important factor in determining the immune response to tumors, but the cause is not known, and the potential interplay between ITH and tumor mutational burden (TMB) is unclear. In a cohort of patients with melanoma, Wolf, Bartok, and colleagues found that those with low levels of ITH had improved survival rates compared with those with higher levels of ITH. When injected into immunocompetent mice, melanoma cells exposed to UVB irradiation (which increases both ITH and TMB) formed tumors that grew at an increased rate compared with non-irradiated melanoma cells. To distinguish between the effects of ITH and TMB, single-cell clones (SCC) from the UVB-irradiated melanoma cells were generated. Injected SCCs formed tumors that grew at reduced rates compared with tumors grown from the heterogeneous parental cells, indicating that low levels of ITH are associated with decreased tumor aggressiveness independently of any effects of TMB. In severely immunocompromised mice, tumors grown from SCCs exhibited as much growth as those grown from the high-ITH, UVB-irradiated parental cells, implying that it was immune rejection that caused the reduced growth of SCC-derived tumors in the immunocompetent mice used in the prior experiments. Correspondingly, SCC-derived tumors were more immunogenic than tumors derived from the high-ITH parental cells. Experiments in which tumors were derived from defined mixtures of different SCC populations revealed that tumor aggressiveness could be largely explained by both the number of clones injected and their genetic diversity. Highlighting the potential clinical relevance of these findings, a meta-analysis of data from patients with melanoma from four prior studies showed that the number of clones and their genetic diversity mediated response to immunotherapy, with tumors having higher diversity being associated with worse outcomes. Collectively, these data establish ITH as an independent factor that may be associated with prognosis and response to immunotherapy and suggest that this phenomenon can be explained by increased immunogenicity of low-ITH tumors.
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