title: Foxp3(+) cell infiltration and granzyme B(+)/Foxp3(+) cell ratio are associated with outcome in neoadjuvant chemotherapy-treated ovarian carcinoma.
abstract: Preoperative neoadjuvant chemotherapy (NAC) can significantly reduce tumour burden in patients with primarily unresectable chemosensitive tumours, allowing a more complete cytoreduction during debulking surgery and facilitating evaluation of tumour chemosensitivity, identification of appropriate treatment options and improvement of intervention protocols. In this study, we investigate, using immunohistochemistry, the impact of platinum/taxane-based NAC (NAC) on tumour-infiltrating lymphocytes (TILs) in advanced epithelial ovarian cancer (EOC) and their relationship with clinical outcome. All patients had clinical response, as shown by ascites volume and CA125 levels compared to pre-treatment findings. NAC intervention significantly increased CD4(+), CD8(+) and granzyme B(+) infiltration while Foxp3(+) accumulation remained unaffected. TILs were prognostically neutral for both progression-free survival (PFS) and overall survival (OS) before NAC. In contrast, after NAC, elevated granzyme B(+) infiltration displayed a tendency for improved PFS (log-rank 0.064). Further, low Foxp3(+) cell density was associated with longer PFS, as compared with strong Foxp3(+) infiltration (median 20.94 vs. 11.24 months; log-rank 0.0001) and with improved OS (median 30.75 vs. 16.04 months, respectively; log-rank 0.056), demonstrating clear prognostic significance for PFS. In addition, high granzyme B(+)/Foxp3(+) ratio post-NAC strongly correlated with improved PFS compared to low granzyme B(+)/Foxp3(+) cell ratio (median 17.88 vs. 11.24 months, respectively), and showed to be a favourable prognostic factor for PFS (log-rank 0.014). Our findings indicate that NAC elicited an immunologic profile in which low immunosuppressive Foxp3(+) infiltration and elevated numbers of activated granzyme B(+) cells were significantly associated with EOC-specific PFS, suggesting a contribution of immunologic effects to improved clinical outcome.
authors.affiliation: Department of Gynaecology and Obstetrics, Centre for Integrated Oncology Bonn, Bonn University Medical Centre, Sigmund Freud-Str. 25, 53105, Bonn, Germany. martin.poelcher@ukb.uni-bonn.de
authors.forename: Martin
authors.initials: M
authors.lastname: Pölcher
authors.forename: Michael
authors.initials: M
authors.lastname: Braun
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Friedrichs
authors.forename: Christian
authors.initials: C
authors.lastname: Rudlowski
authors.forename: Eva
authors.initials: E
authors.lastname: Bercht
authors.forename: Rolf
authors.initials: R
authors.lastname: Fimmers
authors.forename: Axel
authors.initials: A
authors.lastname: Sauerwald
authors.forename: Mignon-Denise
authors.initials: MD
authors.lastname: Keyver-Paik
authors.forename: Kirsten
authors.initials: K
authors.lastname: Kübler
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.forename: Walther C
authors.initials: WC
authors.lastname: Kuhn
authors.forename: Juan-José
authors.initials: JJ
authors.lastname: Hernando
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D018450:Disease Progression; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D053804:Granzymes / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D017671:Platinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D011379:Prognosis; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D017671:Platinum Compounds; D043823:Taxoids; D053804:Granzymes