Wolf, Y;
Bartok, O;
Patkar, S;
Bar Eli, G;
Cohen, S;
Litchfield, K;
Levy, R;
... Samuels, Y; + view all
(2019)
UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma.
Cell
, 179
(1)
219-235.e21.
10.1016/j.cell.2019.08.032.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.cell.2019.08.032 |
| Publisher version: | https://doi.org/10.1016/j.cell.2019.08.032 |
| Language: | English |
| Additional information: | © 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | anti-tumor immunity, intra-tumor heterogeneity, mutational loadmelanoma, cancer neoantigens, checkpoint immunotherapy, mouse model |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10089170 |
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