title: CD103+ intraepithelial T cells in high-grade serous ovarian cancer are phenotypically diverse TCRαβ+ CD8αβ+ T cells that can be targeted for cancer immunotherapy.
abstract: CD103+ tumor-infiltrating lymphocytes (TIL) have been linked to specific epithelial infiltration and a prolonged survival in high-grade serous epithelial ovarian cancer (HGSC). However, whether these cells are induced as part of an ongoing anti-HGSC immune response or represent non-specifically expanded resident or mucosal lymphocytes remains largely unknown. In this study, we first confirmed that CD103+ TIL from HGSC were predominantly localized in the cancer epithelium and were strongly correlated with an improved prognosis. We further demonstrate that CD103+ TIL were almost exclusively CD3+ TCRαβ+ CD8αβ+ CD4- T cells, but heterogeneously expressed T cell memory and differentiation markers. Activation of peripheral T cells in the presence of HGSC was sufficient to trigger induction of CD103 in over 90% of all CD8+ cells in a T cell receptor (TCR)- and TGFβR1-dependent manner. Finally, CD103+ TIL isolated from primary HGSC showed signs of recent activation and dominantly co-expressed key immunotherapeutic targets PD-1 and CD27. Taken together, our data indicate CD103+ TIL in HGSC are formed as the result of an adaptive anti-tumor immune response that might be reactivated by (dual) checkpoint inhibition.
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands.
authors.forename: Fenne L
authors.initials: FL
authors.lastname: Komdeur
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands.|University of Groningen, University Medical Center Groningen, Department of Medical Microbiology, The Netherlands.
authors.forename: Maartje C A
authors.initials: MC
authors.lastname: Wouters
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands.
authors.forename: Hagma H
authors.initials: HH
authors.lastname: Workel
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands.
authors.forename: Aline M
authors.initials: AM
authors.lastname: Tijans
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands.
authors.forename: Anouk L J
authors.initials: AL
authors.lastname: Terwindt
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands.
authors.forename: Kim L
authors.initials: KL
authors.lastname: Brunekreeft
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands.
authors.forename: Annechien
authors.initials: A
authors.lastname: Plat
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands.
authors.forename: Harry G
authors.initials: HG
authors.lastname: Klip
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands.
authors.forename: Florine A
authors.initials: FA
authors.lastname: Eggink
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands.
authors.forename: Ninke
authors.initials: N
authors.lastname: Leffers
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Surgery, The Netherlands.
authors.forename: Wijnand
authors.initials: W
authors.lastname: Helfrich
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Surgery, The Netherlands.
authors.forename: Douwe F
authors.initials: DF
authors.lastname: Samplonius
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Surgery, The Netherlands.
authors.forename: Edwin
authors.initials: E
authors.lastname: Bremer
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands.
authors.forename: G Bea A
authors.initials: GB
authors.lastname: Wisman
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Medical Microbiology, The Netherlands.
authors.forename: Toos
authors.initials: T
authors.lastname: Daemen
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pathology, The Netherlands.
authors.forename: Evelien W
authors.initials: EW
authors.lastname: Duiker
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pathology, The Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: Hollema
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands.
authors.forename: Hans W
authors.initials: HW
authors.lastname: Nijman
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: de Bruyn
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes; D005260:Female; D006801:Humans; D007167:Immunotherapy; D016219:Immunotherapy, Adoptive; D039001:Integrin alpha Chains / Q000378:metabolism*; D000075942:Intraepithelial Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D016246:Lymphocytes, Tumor-Infiltrating; D060787:Neoplasm Grading; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D010641:Phenotype; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; D039001:Integrin alpha Chains; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018125:Receptors, Transforming Growth Factor beta; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; C091367:alpha E integrins; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: CD103; TGF-β; cancer immunotherapy; high-grade serous ovarian cancer; tumor-infiltrating lymphocytes