title: Treatment Regimen, Surgical Outcome, and T-cell Differentiation Influence Prognostic Benefit of Tumor-Infiltrating Lymphocytes in High-Grade Serous Ovarian Cancer.
abstract: OBJECTIVE
  Tumor-infiltrating lymphocytes (TIL) are associated with a better prognosis in high-grade serous ovarian cancer (HGSC). However, it is largely unknown how this prognostic benefit of TIL relates to current standard treatment of surgical resection and (neo-)adjuvant chemotherapy. To address this outstanding issue, we compared TIL infiltration in a unique cohort of patients with advanced-stage HGSC primarily treated with either surgery or neoadjuvant chemotherapy.
  
  
  METHODS
  Tissue microarray slides containing samples of 171 patients were analyzed for CD8(+) TIL by IHC. Freshly isolated CD8(+) TIL subsets were characterized by flow cytometry based on differentiation, activation, and exhaustion markers. Relevant T-cell subsets (CD27(+)) were validated using IHC and immunofluorescence.
  
  
  RESULTS
  A prognostic benefit for patients with high intratumoral CD8(+) TIL was observed if primary surgery had resulted in a complete cytoreduction (no residual tissue). By contrast, optimal (<1 cm of residual tumor) or incomplete cytoreduction fully abrogated the prognostic effect of CD8(+) TIL. Subsequent analysis of primary TIL by flow cytometry and immunofluorescence identified CD27 as a key marker for a less-differentiated, yet antigen-experienced and potentially tumor-reactive CD8(+) TIL subset. In line with this, CD27(+) TIL were associated with an improved prognosis even in incompletely cytoreduced patients. Neither CD8(+) nor CD27(+) cell infiltration was of prognostic benefit in patients treated with neoadjuvant chemotherapy.
  
  
  CONCLUSIONS
  Our findings indicate that treatment regimen, surgical result, and the differentiation of TIL should all be taken into account when studying immune factors in HGSC or, by extension, selecting patients for immunotherapy trials.
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. h.w.nijman@umcg.nl.
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: Fenne L
authors.initials: FL
authors.lastname: Komdeur
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: 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: Annechien
authors.initials: A
authors.lastname: Plat
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Medical Oncology, The Netherlands.
authors.forename: Neeltje M
authors.initials: NM
authors.lastname: Kooi
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: 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: 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: Refika
authors.initials: R
authors.lastname: Yigit
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Medical Oncology, The Netherlands.
authors.forename: Steven
authors.initials: S
authors.lastname: de Jong
authors.affiliation: Leiden University Medical Center (LUMC), Department of Immunohematology and Blood Transfusion, The Netherlands. ISA Pharmaceuticals, Leiden, The Netherlands.
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
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 Pathology, The Netherlands.
authors.forename: Evelien W
authors.initials: EW
authors.lastname: Duiker
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 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.
authors.forename: Hans W
authors.initials: HW
authors.lastname: Nijman
mesh_terms: D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D015415:Biomarkers; D002454:Cell Differentiation; D003131:Combined Modality Therapy; D018284:Cystadenocarcinoma, Serous / Q000276:immunology* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D010641:Phenotype; D011379:Prognosis; D016016:Proportional Hazards Models; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D015703:Antigens, CD; D015415:Biomarkers