Analyzing TCGA melanoma data, Wolf and Bartok et al. found that lower intratumor heterogeneity (ITH), but not higher tumor mutational burden (TMB), correlated with antitumor immunity and survival. UVB irradiation of B2905 mouse melanoma cells increased ITH and tumor growth despite higher TMB, but single-cell subclones of this line had increased cytotoxic CD8+ T cell infiltration and were rejected in vivo. Mixed-population tumors with greater subclone numbers or genetic diversity grew faster, independent of TMB. In a meta-analysis of recent immune checkpoint trials in melanoma, patients with lower ITH showed extended survival.
Contributed by Alex Najibi
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 Info: (1) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (2) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Author Info: (1) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (2) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (3) Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (4) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (5) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (6) Cancer Evolution and Genome Instability Laboratory, Francis Crick Institute, London NW1 1AT, UK; Cancer Research UK Lung Cancer Centre of Excellence London, University College London Cancer Institute, London WC1E 6DD, UK. (7) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (8) Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE , UK. (9) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (10) Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (11) Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (12) Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel. (13) Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (14) The Lautenberg Center for Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel. (15) The Lautenberg Center for Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel. (16) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (17) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (18) Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (19) Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel. (20) Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel. (21) Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE , UK. (22) Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (23) The Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel. (24) The Lautenberg Center for Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel. (25) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (26) Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel. (27) Cancer Evolution and Genome Instability Laboratory, Francis Crick Institute, London NW1 1AT, UK; Cancer Research UK Lung Cancer Centre of Excellence London, University College London Cancer Institute, London WC1E 6DD, UK; Department of Medical Oncology, University College London Hospitals, London NW1 2BU, UK. (28) Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. Electronic address: eyruppin@gmail.com. (29) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. Electronic address: yardena.samuels@weizmann.ac.il.
