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UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma.

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.

journal_name

Cell

journal_title

Cell

authors

Wolf Y,Bartok O,Patkar S,Eli GB,Cohen S,Litchfield K,Levy R,Jiménez-Sánchez A,Trabish S,Lee JS,Karathia H,Barnea E,Day CP,Cinnamon E,Stein I,Solomon A,Bitton L,Pérez-Guijarro E,Dubovik T,Shen-Orr SS,Miller ML,Me

doi

10.1016/j.cell.2019.08.032

subject

Has Abstract

pub_date

2019-09-19 00:00:00

pages

219-235.e21

issue

1

eissn

0092-8674

issn

1097-4172

pii

S0092-8674(19)30951-1

journal_volume

179

pub_type

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