However, tumors containing equally high TMB levels exhibit a variable immune response ( Rooney et al., 2015), and some cancers with a low TMB do still respond to immunotherapy ( Miao et al., 2018a), which brings into question the association between TMB and immune response. The leading hypothesis in the immunotherapy field is that tumors with increased TMB present more neoantigens and, thus, are more immunogenic ( Germano et al., 2017, Gubin et al., 2015, Hellmann et al., 2018, Rizvi et al., 2015, Strønen et al., 2016, Van Allen et al., 2015). Furthermore, T cell activation and dysfunctional states are essential for controlling tumor immunity ( Chihara et al., 2018, Kurtulus et al., 2019, Li et al., 2019, Sade-Feldman et al., 2018). There is a growing appreciation of the key role of T cells responding to neoantigens in the efficacy of melanoma therapy ( Gros et al., 2016, Gubin et al., 2014, Rooney et al., 2015, Strønen et al., 2016). Cutaneous melanoma, which is among the most highly mutated malignancies ( Alexandrov et al., 2013), has the highest objective response rates to checkpoint blockade (∼60% upon combined CTLA-4 and PD-1 blockade Larkin et al., 2015). Indeed, a high tumor mutational burden (TMB) and neoantigen load in tumors have been associated with an enhanced response to immune checkpoint blockade therapy ( Chan et al., 2019, Germano et al., 2017, Hellmann et al., 2018, Samstein et al., 2019, Snyder et al., 2014, Van Allen et al., 2015). Neoantigens that arise as a consequence of somatic mutations within the tumor represent an attractive means to promote immune recognition in cancer ( Gubin et al., 2014). However, many tumors do not respond to checkpoint inhibitors, and the determinants of treatment efficacy remain largely unknown ( Sharma et al., 2017). It has recently been shown that immunotherapy strategies that enhance the anti-tumor T cell response, such as checkpoint inhibitors and adoptive T cell therapy, have remarkable clinical effects in a wide range of tumor types ( Ribas and Wolchok, 2018, Wolf and Samuels, 2018). 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. Our analysis of melanoma patient tumor data recapitulates our results in terms of overall survival and response to immune checkpoint therapy. 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. Their rejection is accompanied by increased T cell reactivity and a less suppressive microenvironment. However, single-cell-derived tumors with reduced ITH are swiftly rejected. Induction of UVB-derived mutations yields highly aggressive tumors with decreased anti-tumor activity. 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. Although clonal neo-antigen burden is associated with improved response to immune therapy, the functional basis for this remains unclear.
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