UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma

Yochai Wolf, Osnat Bartok, Sushant Patkar, Gitit Bar Eli, Sapir Cohen, Kevin Litchfield, Ronen Levy, Alejandro Jiménez-Sánchez, Sophie Trabish, Joo Sang Lee, Hiren Karathia, Eilon Barnea, Chi Ping Day, Einat Cinnamon, Ilan Stein, Adam Solomon, Lital Bitton, Eva Pérez-Guijarro, Tania Dubovik, Shai S. Shen-OrrMartin L. Miller, Glenn Merlino, Yishai Levin, Eli Pikarsky, Lea Eisenbach, Arie Admon, Charles Swanton, Eytan Ruppin*, Yardena Samuels

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)219-235.e21
JournalCell
Volume179
Issue number1
DOIs
StatePublished - 19 Sep 2019
Externally publishedYes

Funding

FundersFunder number
Apogen Biotechnologies
Epic Bioscience
GRAIL
Hamburger family
Knell Family
Medicxi Advisor for Dynamo Therapeutics
Roche Ventana
Roche-Ventana
National Institutes of Health
National Cancer Institute
Bristol-Myers Squibb
Pfizer
AstraZeneca
Genentech
Wellcome TrustC14303/A17197
Horizon 2020 Framework Programme
Medical Research CouncilMR/P014712/1
Cancer Research UKFC001169, FC001202
University College London
European Research Council
Weizmann Institute of Science
Consejo Nacional de Ciencia y Tecnología
Israel Science Foundation696/17
Université de Lausanne
Horizon 2020770854
Rising Tide Foundation
Cancer Research UK Cambridge Institute, University of Cambridge

    Keywords

    • anti-tumor immunity
    • cancer neoantigens
    • checkpoint immunotherapy
    • intra-tumor heterogeneity
    • melanoma
    • mouse model
    • mutational load

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