@article{e4e5a7efce0f423bbdd37cdad1c2fa2d,
title = "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.",
author = "Yochai Wolf and Osnat Bartok and Sushant Patkar and Eli, {Gitit Bar} and Sapir Cohen and Kevin Litchfield and Ronen Levy and Alejandro Jim{\'e}nez-S{\'a}nchez and Sophie Trabish and Lee, {Joo Sang} and Hiren Karathia and Eilon Barnea and Chi-Ping Day and Einat Cinnamon and Ilan Stein and Adam Solomon and Lital Bitton and Eva P{\'e}rez-Guijarro and Tania Dubovik and Shen-Orr, {Shai S} and Miller, {Martin L} and Glenn Merlino and Yishai Levin and Eli Pikarsky and Lea Eisenbach and Arie Admon and Charles Swanton and Eytan Ruppin and Yardena Samuels",
note = "We would like to thank S. Motola and M. Gershovis (Israel National Center for Personalized Medicine) for their help with the WES and the INCPM proteomic unit for their assistance with the proteomic analysis, Prof. Jung (Immunology Department, Weizmann Institute of Science) for the CD80/86−/− mice, Dr. Harmelin (veterinary resources, Weizmann Institute of Science) for help with pathologic assessment of histology, Dr. Bassani-Sternberg (University of Lausanne) for assistance with peptidomics analysis, Dr. McGranahan (University College London) and R. Rosenthal (Francis Crick Institute) for assistance with clonality analysis, and Dr. A. Snir-Wolf for fruitful discussions. Y.S. is supported by Israel Science Foundation grant 696/17, the European Research Council (ERC) under the European Union Horizon 2020 Research and Innovation Program (grant agreement 770854), the ERC (CoG-770854), The Rising Tide Foundation, the Knell family, and the Hamburger family. Y.W. is supported by a Fienberg School Dean of Faculty fellowship. A.J.-S. is supported by the Cancer Research UK Cambridge Institute and the Mexican National Council of Science and Technology (CONACyT). C.S. is Royal Society Napier Research Professor. This work was supported by the Francis Crick Institute that receives its core funding from Cancer Research UK (FC001169, FC001202), the UK Medical Research Council (FC001169, FC001202), and the Wellcome Trust (FC001169, FC001202). M.L.M. is supported by a Cancer Research UK core grant (C14303/A17197). K.L. is funded by a Skills Development Fellowship from the UK Medical Research Council (MR/P014712/1). G.M., C.P.D., and E.P.G. were funded by the Intramural Research Program, NCI, NIH. E.R. is supported by NIH intramural funds. Author Contributions Y.W., O.B., G.B.E., S.C., S.T., and A.S. conducted in vitro and in vivo experiments. S.P., H.K., J.S.L., R.L. and E.R. performed in-depth analysis of human TCGA and immunotherapy patient data. A.J.-S., R.L., and M.L.M. analyzed WES of mouse samples. K.L. performed the phylogenetic tree analysis and provided additional bioinformatics data analysis support. C.S. performed data interpretation of mouse phylogenetic results. Y.L., E.B., R.L., and A.A. performed and analyzed mass spectrometry data. R.L. analyzed bioinformatics data. C.-P.D., E.P.-G., and G.M. provided crucial material. E.C., I.S., and E.P. performed and analyzed immunohistochemistry. L.B., T.D., S.S.S.-O., and L.E. provided technical help and advice. Y.W., O.B., E.R., and Y.S. conceived the project and wrote the manuscript. All authors contributed to the final version of the paper.",
year = "2019",
month = sep,
day = "19",
doi = "10.1016/j.cell.2019.08.032",
language = "الإنجليزيّة",
volume = "179",
pages = "219--235",
journal = "Cell",
issn = "0092-8674",
publisher = "Elsevier B.V.",
number = "1",
}