title: Tumor-infiltrating lymphocytes expressing the tissue resident memory marker CD103 are associated with increased survival in high-grade serous ovarian cancer.
abstract: BACKGROUND
  The presence of CD8(+) tumor-infiltrating lymphocytes (TIL) is associated with prolonged survival in high-grade serous ovarian cancer (HGSC) and other epithelial cancers. Survival is most strongly associated with intraepithelial versus intrastromal CD8(+) TILs; however, the mechanisms that promote the intraepithelial localization of TILs remain poorly understood. We hypothesized that intraepithelial CD8(+) TILs, like normal mucosal intraepithelial lymphocytes, might express CD103, a subunit of αE/β7 integrin, which binds E-cadherin on epithelial cells.
  
  
  METHODS
  A large collection of primary ovarian tumors (HGSC, endometrioid, mucinous, and clear cell) was analyzed by immunohistochemistry for the presence of TIL-expressing CD103. The activation and differentiation status of CD103(+) TILs were assessed by flow cytometry. The prognostic significance of TIL subsets was evaluated by Kaplan-Meier analysis.
  
  
  RESULTS
  CD103(+) TILs were present in all major ovarian cancer subtypes and were most abundant in HGSC. CD103(+) TILs were preferentially localized to epithelial regions of tumors and were comprised predominantly of CD8(+) T cells expressing activation (HLA-DR, Ki-67, PD-1) and cytolytic (TIA-1) markers, as well as CD56(+) NK cells. Tumor infiltration by CD103(+) TILs was strongly associated with patient survival in HGSC. Tumors containing CD8(+) TILs that were CD103(-) showed poor prognosis equivalent to tumors lacking CD8(+) TILs altogether.
  
  
  CONCLUSIONS
  CD103(+) TILs comprise intraepithelial, activated CD8(+) T cells, and NK cells and are strongly associated with patient survival in HGSC. CD103 may serve as a useful marker for enriching the most beneficial subsets of TILs for immunotherapy.
authors.affiliation: Authors' Affiliations: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency; Department of Biochemistry and Microbiology, University of Victoria; Departments of Pathology and Laboratory Medicine and Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Webb
authors.forename: Katy
authors.initials: K
authors.lastname: Milne
authors.forename: Peter
authors.initials: P
authors.lastname: Watson
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Deleeuw
authors.forename: Brad H
authors.initials: BH
authors.lastname: Nelson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism*; D019002:CD56 Antigen / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018284:Cystadenocarcinoma, Serous / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D004848:Epithelium / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007156:Immunologic Memory; D039001:Integrin alpha Chains / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism*; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology
chemical_list: D015703:Antigens, CD; D019002:CD56 Antigen; D039001:Integrin alpha Chains; C091367:alpha E integrins