title: Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy.
abstract: Immunotherapies based on immune checkpoint blockade are highly effective in a subset of patients. An ongoing challenge is the identification of biomarkers that predict which patients will benefit from these therapies. Aneuploidy, also known as somatic copy number alterations (SCNAs), is widespread in cancer and is posited to drive tumorigenesis. Analyzing 12 human cancer types, we find that, for most, highly aneuploid tumors show reduced expression of markers of cytotoxic infiltrating immune cells, especially CD8+T cells, and increased expression of cell proliferation markers. Different types of SCNAs predict the proliferation and immune signatures, implying distinct underlying mechanisms. Using published data from two clinical trials of immune checkpoint blockade therapy for metastatic melanoma, we found that tumor aneuploidy inversely correlates with patient survival. Together with other tumor characteristics such as tumor mutational load, aneuploidy may thus help identify patients most likely to respond to immunotherapy.
authors.affiliation: Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Davoli
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA 02215-5450, USA.
authors.forename: Hajime
authors.initials: H
authors.lastname: Uno
authors.affiliation: Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Wooten
authors.affiliation: Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA. selledge@genetics.med.harvard.edu.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
mesh_terms: D014408:Biomarkers, Tumor / Q000276:immunology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D002453:Cell Cycle / Q000276:immunology; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D056915:DNA Copy Number Variations; D006801:Humans; D007167:Immunotherapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D017354:Point Mutation; D011379:Prognosis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D059467:Transcriptome; D019139:Tumor Escape / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human