title: POLE Proofreading Mutations Elicit an Antitumor Immune Response in Endometrial Cancer.
abstract: OBJECTIVE
  Recent studies have shown that 7% to 12% of endometrial cancers are ultramutated due to somatic mutation in the proofreading exonuclease domain of the DNA replicase POLE. Interestingly, these tumors have an excellent prognosis. In view of the emerging data linking mutation burden, immune response, and clinical outcome in cancer, we investigated whether POLE-mutant endometrial cancers showed evidence of increased immunogenicity.
  
  
  METHODS
  We examined immune infiltration and activation according to tumor POLE proofreading mutation in a molecularly defined endometrial cancer cohort including 47 POLE-mutant tumors. We sought to confirm our results by analysis of RNAseq data from the TCGA endometrial cancer series and used the same series to examine whether differences in immune infiltration could be explained by an enrichment of immunogenic neoepitopes in POLE-mutant endometrial cancers.
  
  
  RESULTS
  Compared with other endometrial cancers, POLE mutants displayed an enhanced cytotoxic T-cell response, evidenced by increased numbers of CD8(+) tumor-infiltrating lymphocytes and CD8A expression, enrichment for a tumor-infiltrating T-cell gene signature, and strong upregulation of the T-cell cytotoxic differentiation and effector markers T-bet, Eomes, IFNG, PRF, and granzyme B. This was accompanied by upregulation of T-cell exhaustion markers, consistent with chronic antigen exposure. In silico analysis confirmed that POLE-mutant cancers are predicted to display more antigenic neoepitopes than other endometrial cancers, providing a potential explanation for our findings.
  
  
  CONCLUSIONS
  Ultramutated POLE proofreading-mutant endometrial cancers are characterized by a robust intratumoral T-cell response, which correlates with, and may be caused by an enrichment of antigenic neopeptides. Our study provides a plausible mechanism for the excellent prognosis of these cancers.
authors: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Postbus 9600, 2300 RC Leiden, The Netherlands.
authors: Inge C
authors: IC
authors: van Gool
authors: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, PO 30.001 9700 RB Groningen, The Netherlands.
authors: Florine A
authors: FA
authors: Eggink
authors: Molecular and Population Genetics Laboratory, The Wellcome Trust Centre for Human Genetics, University of Oxford. Roosevelt Drive, Oxford, OX3 7BN, UK.
authors: Luke
authors: L
authors: Freeman-Mills
authors: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Postbus 9600, 2300 RC Leiden, The Netherlands.
authors: Ellen
authors: E
authors: Stelloo
authors: Immunity Theme, NIHR Oxford Comprehensive Biomedical Research Centre, The Peter Medawar Building for Pathogen Research, University of Oxford, South Parks Road, Oxford, OX1 3SY, UK.
authors: Emanuele
authors: E
authors: Marchi
authors: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, PO 30.001 9700 RB Groningen, The Netherlands.
authors: Marco
authors: M
authors: de Bruyn
authors: Molecular and Population Genetics Laboratory, The Wellcome Trust Centre for Human Genetics, University of Oxford. Roosevelt Drive, Oxford, OX3 7BN, UK.
authors: Claire
authors: C
authors: Palles
authors: Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, Postbus 9600, 2300 RC Leiden, The Netherlands.
authors: Remi A
authors: RA
authors: Nout
authors: Department of Gynecology, Leiden University Medical Center, Albinusdreef 2, Postbus 9600, 2300 RC Leiden, The Netherlands.
authors: Cor D
authors: CD
authors: de Kroon
authors: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Postbus 9600, 2300 RC Leiden, The Netherlands.
authors: Elisabeth M
authors: EM
authors: Osse
authors: Immunity Theme, NIHR Oxford Comprehensive Biomedical Research Centre, The Peter Medawar Building for Pathogen Research, University of Oxford, South Parks Road, Oxford, OX1 3SY, UK.
authors: Paul
authors: P
authors: Klenerman
authors: Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, Postbus 9600, 2300 RC Leiden, The Netherlands.
authors: Carien L
authors: CL
authors: Creutzberg
authors: Molecular and Population Genetics Laboratory, The Wellcome Trust Centre for Human Genetics, University of Oxford. Roosevelt Drive, Oxford, OX3 7BN, UK.|Genomic Medicine Theme, Oxford Comprehensive Biomedical Research Centre, The Wellcome Trust Centre for Human Genetics, University of Oxford. Roosevelt Drive, Oxford, OX3 7BN, UK.
authors: Ian Pm
authors: IP
authors: Tomlinson
authors: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Postbus 9600, 2300 RC Leiden, The Netherlands.
authors: Vincent Thbm
authors: VT
authors: Smit
authors: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, PO 30.001 9700 RB Groningen, The Netherlands.
authors: Hans W
authors: HW
authors: Nijman
authors: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Postbus 9600, 2300 RC Leiden, The Netherlands.
authors: Tjalling
authors: T
authors: Bosse
authors: Molecular and Population Genetics Laboratory, The Wellcome Trust Centre for Human Genetics, University of Oxford. Roosevelt Drive, Oxford, OX3 7BN, UK.|Oxford Cancer Centre, Churchill Hospital, Old Road, Oxford OX3 9DU, UK.
authors: David N
authors: DN
authors: Church
mesh_terms: D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004257:DNA Polymerase II / Q000235:genetics* / Q000276:immunology; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D009154:Mutation; D000075223:Poly-ADP-Ribose Binding Proteins; D016133:Polymerase Chain Reaction
chemical_list: D000075223:Poly-ADP-Ribose Binding Proteins; D004257:DNA Polymerase II; C119525:POLE protein, human