title: Immunological profiling of molecularly classified high-risk endometrial cancers identifiesPOLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition.
abstract: High-risk endometrial cancer (EC) is an aggressive disease for which new therapeutic options are needed. Aims of this study were to validate the enhanced immune response in highly mutated ECs and to explore immune profiles in other EC subgroups. We evaluated immune infiltration in 116 high-risk ECs from the TransPORTEC consortium, previously classified into four molecular subtypes: (i) ultramutatedPOLEexonuclease domain-mutant ECs (POLE-mutant); (ii) hypermutated microsatellite unstable (MSI); (iii) p53-mutant; and (iv) no specific molecular profile (NSMP). Within The Cancer Genome Atlas (TCGA) EC cohort, significantly higher numbers of predicted neoantigens were demonstrated inPOLE-mutant and MSI tumors compared with NSMP and p53-mutants. This was reflected by enhanced immune expression and infiltration inPOLE-mutant and MSI tumors in both the TCGA cohort (mRNA expression) and the TransPORTEC cohort (immunohistochemistry) with high infiltration of CD8+(90% and 69%), PD-1+(73% and 69%) and PD-L1+immune cells (100% and 71%). Notably, a subset of p53-mutant and NSMP cancers was characterized by signs of an antitumor immune response (43% and 31% of tumors with high infiltration of CD8+cells, respectively), despite a low number of predicted neoantigens. In conclusion, the presence of enhanced immune infiltration, particularly high numbers of PD-1 and PD-L1 positive cells, in highly mutated, neoantigen-richPOLE-mutant and MSI endometrial tumors suggests sensitivity to immune checkpoint inhibitors.
authors.affiliation: Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen , Groningen, the Netherlands.
authors.forename: Florine A
authors.initials: FA
authors.lastname: Eggink
authors.affiliation: Department of Pathology, Leiden University Medical Center , Leiden, the Netherlands.
authors.forename: Inge C
authors.initials: IC
authors.lastname: Van Gool
authors.affiliation: Department of Medical Oncology, INSERM U981, Gustave Roussy Cancer Center , Villejuif, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Leary
authors.affiliation: Queensland University of Technology (QUT), Translational Research Institute , Brisbane, QLD, Australia.
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Pollock
authors.affiliation: Institute of Cancer Sciences, University of Manchester, St Marys Hospital , Manchester, UK.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Crosbie
authors.affiliation: Division of Cancer Medicine, Peter MacCallum Cancer Centre , East Melbourne, VIC, Australia.
authors.forename: Linda
authors.initials: L
authors.lastname: Mileshkin
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands; Center for Gynecological Oncology Amsterdam, VU Medical Center, Amsterdam, the Netherlands.
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
authors.affiliation: Department of Medical Oncology, INSERM U981, Gustave Roussy Cancer Center , Villejuif, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Adam
authors.affiliation: Tumour Genomics and Immunology Group, Oxford Centre for Cancer Gene Research, The Wellcome Trust Centre for Human Genetics, University of Oxford , Oxford, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Freeman-Mills
authors.affiliation: Tumour Genomics and Immunology Group, Oxford Centre for Cancer Gene Research, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Oxford Cancer Centre, Churchill Hospital, Oxford, UK.
authors.forename: David N
authors.initials: DN
authors.lastname: Church
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center , Leiden, the Netherlands.
authors.forename: Carien L
authors.initials: CL
authors.lastname: Creutzberg
authors.affiliation: Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen , Groningen, the Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: De Bruyn
authors.affiliation: Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen , Groningen, the Netherlands.
authors.forename: Hans W
authors.initials: HW
authors.lastname: Nijman
authors.affiliation: Department of Pathology, Leiden University Medical Center , Leiden, the Netherlands.
authors.forename: Tjalling
authors.initials: T
authors.lastname: Bosse
keywords: Checkpoint inhibition; endometrial cancer; high-risk; molecular classification; tumor-infiltrating lymphocytes