title: CD103 defines intraepithelial CD8+ PD1+ tumour-infiltrating lymphocytes of prognostic significance in endometrial adenocarcinoma.
abstract: Intraepithelial CD8+ tumour-infiltrating T-lymphocytes (TIL) are associated with a prolonged survival in endometrial cancer (EC). By contrast, stromal infiltration of CD8+ TIL does not confer prognostic benefit. A single marker to discriminate these populations would therefore be of interest for rapid assessment of the tumour immune contexture, ex vivo analysis of intraepithelial and stromal T-cells on a functional level and/or adoptive T-cell transfer. Here we determined whether CD103, the αE subunit of the αEβ7integrin, can be used to specifically discriminate the epithelial and stromal CD8+ TIL populations in EC.
  
  
  
  CD103+ TIL were quantified in a cohort of 305 EC patients by immunohistochemistry. Localization of CD103+ cells and co-expression of CD103 with CD3, CD8, CD16 and FoxP3 were assessed by immunofluorescence. Further phenotyping of CD103+ cells was performed by flow cytometry on primary endometrial tumour digests.
  
  
  
  CD8+CD103+ cells were preferentially located in endometrial tumour epithelium, whereas CD8+CD103- cells were located in stroma. CD103+ lymphocytes were predominantly CD3+CD8+ T-cells and expressed PD1. The presence of a high CD103+ cell infiltration was associated with an improved prognosis in patients with endometrial adenocarcinoma (p = 0.035). Moreover, this beneficial effect was particularly evident in high-risk adenocarcinoma patients (p = 0.031).
  
  
  
  Because of the restricted expression on intraepithelial CD8+ T-cells, CD103 may be a suitable biomarker for rapid assessment of immune infiltration of epithelial cancers. Furthermore, this intraepithelial tumour-reactive subset might be an interesting T-cell subset for adoptive T-cell transfer and/or target for checkpoint inhibition therapy.
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: 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: 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: G Bea A
authors.initials: GB
authors.lastname: Wisman
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands.
authors.forename: Henriette J G
authors.initials: HJ
authors.lastname: Arts
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands.
authors.forename: Maaike H M
authors.initials: MH
authors.lastname: Oonk
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands.
authors.forename: Marian J E
authors.initials: MJ
authors.lastname: Mourits
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands.
authors.forename: Refika
authors.initials: R
authors.lastname: Yigit
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: Versluis
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: Marco
authors.initials: M
authors.lastname: de Bruyn
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, The Netherlands. Electronic address: h.w.nijman@umcg.nl.
authors.forename: Hans W
authors.initials: HW
authors.lastname: Nijman
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000628:therapy; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016889:Endometrial Neoplasms / Q000276:immunology* / Q000628:therapy; D005260:Female; D006801:Humans; D039001:Integrin alpha Chains / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D015703:Antigens, CD; D039001:Integrin alpha Chains; D016023:Integrins; C091367:alpha E integrins; C071777:integrin alpha4beta7
keywords: Adenocarcinoma; CD103; Endometrial cancer; Survival; Tumour-infiltrating lymphocytes