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-Orr; Martin L. Miller; Glenn Merlino; Yishai Levin; Eli Pikarsky; Lea Eisenbach; Arie Admon; Charles Swanton; Eytan Ruppin; Yardena Samuels

doi:10.1016/j.cell.2019.08.032

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

Department of Immunology and Cancer Research

Research output: Contribution to journal › Article › peer-review

242 Scopus citations

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 language	English
Pages (from-to)	219-235.e21
Journal	Cell
Volume	179
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2019.08.032
State	Published - 19 Sep 2019

Bibliographical note

Funding Information:
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. 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. C.S. declares the following receipt of grants/research support: Pfizer, AstraZeneca, BMS, Roche Ventana. Receipt of honoraria, consultancy, or SAB Member fees: Pfizer, Novartis, GlaxoSmithKline, MSD, BMS, Celgene, AstraZeneca, Illumina, Sarah Canon Research Institute, Genentech, Roche-Ventana, GRAIL, Medicxi Advisor for Dynamo Therapeutics. Stock shareholder: Apogen Biotechnologies, Epic Bioscience, GRAIL. Co-Founder & stock options: Achilles Therapeutics. K.L. reports speaker fees from Roche Tissue Diagnostics and patents pending on indel burden as a predictor of checkpoint inhibitor response and targeting of frameshift neoantigens for personalised immunotherapy.

Funding Information:
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.

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2019.08.032

Cite this

Wolf, Y., Bartok, O., Patkar, S., Eli, G. B., Cohen, S., Litchfield, K., Levy, R., Jiménez-Sánchez, A., Trabish, S., Lee, J. S., Karathia, H., Barnea, E., Day, C. P., Cinnamon, E., Stein, I., Solomon, A., Bitton, L., Pérez-Guijarro, E., Dubovik, T., ... Samuels, Y. (2019). UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma. Cell, 179(1), 219-235.e21. https://doi.org/10.1016/j.cell.2019.08.032

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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.",

keywords = "anti-tumor immunity, cancer neoantigens, checkpoint immunotherapy, intra-tumor heterogeneity, melanoma, mouse model, mutational load",

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 Day, {Chi Ping} 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",

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year = "2019",

month = sep,

day = "19",

doi = "10.1016/j.cell.2019.08.032",

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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, Merlino, G, Levin, Y, Pikarsky, E, Eisenbach, L, Admon, A, Swanton, C, Ruppin, E & Samuels, Y 2019, 'UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma', Cell, vol. 179, no. 1, pp. 219-235.e21. https://doi.org/10.1016/j.cell.2019.08.032

TY - JOUR

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AU - Wolf, Yochai

AU - Bartok, Osnat

AU - Patkar, Sushant

AU - Eli, Gitit Bar

AU - Cohen, Sapir

AU - Litchfield, Kevin

AU - Levy, Ronen

AU - Jiménez-Sánchez, Alejandro

AU - Trabish, Sophie

AU - Lee, Joo Sang

AU - Karathia, Hiren

AU - Barnea, Eilon

AU - Day, Chi Ping

AU - Cinnamon, Einat

AU - Stein, Ilan

AU - Solomon, Adam

AU - Bitton, Lital

AU - Pérez-Guijarro, Eva

AU - Dubovik, Tania

AU - Shen-Orr, Shai S.

AU - Miller, Martin L.

AU - Merlino, Glenn

AU - Levin, Yishai

AU - Pikarsky, Eli

AU - Eisenbach, Lea

AU - Admon, Arie

AU - Swanton, Charles

AU - Ruppin, Eytan

AU - Samuels, Yardena

PY - 2019/9/19

Y1 - 2019/9/19

N2 - 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.

AB - 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.

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KW - cancer neoantigens

KW - checkpoint immunotherapy

KW - intra-tumor heterogeneity

KW - melanoma

KW - mouse model

KW - mutational load

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UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma

Abstract

Bibliographical note

Keywords

UN SDGs

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