UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma

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. Green open access

[thumbnail of 1-s2.0-S0092867419309511-main.pdf]
Preview
Text
1-s2.0-S0092867419309511-main.pdf - Published Version

Download (9MB) | Preview

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
Downloads since deposit
71Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item