title: Neoadjuvant chemotherapy (NACT) increases immune infiltration and programmed death-ligand 1 (PD-L1) expression in epithelial ovarian cancer (EOC).
abstract: Lymphocytic infiltration at diagnosis is prognostic in EOC, however, the impact of NACT on tumour infiltrating lymphocytes (TILs) or PD-L1 expression remains poorly described.
  
  
  
  Patients with EOC and sequential samples (pre-NACT, post-NACT or relapse) were retrospectively identified. TILs were evaluated on whole sections; stromal TILs (sTILs) scored as percentage of stromal area with high sTILs defined as ≥50%; intra-epithelial TILs (ieTILs) scored semi-quantitatively (0-3) with high ieTILs ≥2. A smaller number were available for PD-L1 evaluation, cut-off for positivity was ≥5% staining.
  
  
  
  sTILs were detected in all tumours at diagnosis (range 2-90%, median 20%), with 22% (25/113) showing high sTILs. Among evaluable paired pre/post-NACT samples (N = 83), an overall increase in median sTILs from 20% to 30% was seen following NACT (P = 0.0005); individually the impact of NACT varied with sTILs increasing in 51% (42/83), decreasing in 25%, and stable in 24%. Post-NACT sTILs were predictive of platinum-free interval (PFI), patients with PFI ≥6 months had significantly higher post-NACT sTILs (sTILs 28% versus 18% for PFI <6 months, P = 0.026); pre-NACT sTILS were not predictive. At diagnosis, 23% showed high ieTILs, and following NACT 33% showed increasing ieTILs. Proportion of tumours with PD-L1-positive immune cells was 30% (15/50) pre-NACT and 53% (27/51) post-NACT (P = 0.026). Among paired tumours, 63% of PD-L1-negative tumours became positive after NACT, furthermore cisplatin induced PD-L1 expression in PD-L1-negative EOC cell lines. On multivariate analysis, high sTILs both pre- and post-NACT were independent prognostic factors for progression-free survival (PFS) (HR 0.49, P = 0.02 and HR 0.60, P = 0.05, respectively). No prognostic impact of ieTILs or PD-L1 expression was detected.
  
  
  
  In EOC, sTILs levels are prognostic at diagnosis and remain prognostic after NACT. TILs and PD-L1 expression increase following NACT. Evaluation of immune parameters in the post-NACT tumour may help select patients for immunotherapy trials.
authors.affiliation: INSERM U981 Gynaecological Tumours, Gustave Roussy Cancer Center, Villejuif.
authors.forename: S J L
authors.initials: SJL
authors.lastname: Mesnage
authors.affiliation: INSERM U981 Gynaecological Tumours, Gustave Roussy Cancer Center, Villejuif.|Faculty of Sciences, University Paris-Sud, Orsay.
authors.forename: A
authors.initials: A
authors.lastname: Auguste
authors.affiliation: INSERM U981 Gynaecological Tumours, Gustave Roussy Cancer Center, Villejuif.|Departments of Biopathology, Gustave Roussy, Villejuif, France.
authors.forename: C
authors.initials: C
authors.lastname: Genestie
authors.affiliation: Department of Biostatistics and Epidemiology, Gustave Roussy, Villejuif, France.
authors.forename: A
authors.initials: A
authors.lastname: Dunant
authors.affiliation: INSERM U981 Gynaecological Tumours, Gustave Roussy Cancer Center, Villejuif.
authors.forename: E
authors.initials: E
authors.lastname: Pain
authors.affiliation: Translational Research and Histocytopathology Laboratory,  Gustave Roussy, 114 rue E Vaillant, 94805, Villejuif, France.
authors.forename: F
authors.initials: F
authors.lastname: Drusch
authors.affiliation: Gustave Roussy, Université Paris-Saclay, Department of Gynecologic Surgery, F-94805, Villejuif, France.
authors.forename: S
authors.initials: S
authors.lastname: Gouy
authors.affiliation: Gustave Roussy, Université Paris-Saclay, Department of Gynecologic Surgery, F-94805, Villejuif, France.
authors.forename: P
authors.initials: P
authors.lastname: Morice
authors.affiliation: Gustave Roussy, Université Paris-Saclay, Department of Gynecologic Surgery, F-94805, Villejuif, France.
authors.forename: E
authors.initials: E
authors.lastname: Bentivegna
authors.affiliation: Oncology, Gustave Roussy Cancer Center, Villejuif, France.
authors.forename: C
authors.initials: C
authors.lastname: Lhomme
authors.affiliation: Oncology, Gustave Roussy Cancer Center, Villejuif, France.
authors.forename: P
authors.initials: P
authors.lastname: Pautier
authors.affiliation: Oncology, Gustave Roussy Cancer Center, Villejuif, France.
authors.forename: J
authors.initials: J
authors.lastname: Michels
authors.affiliation: INSERM U981 Gynaecological Tumours, Gustave Roussy Cancer Center, Villejuif.|Faculty of Sciences, University Paris-Sud, Orsay.
authors.forename: A
authors.initials: A
authors.lastname: Le Formal
authors.affiliation: Oncology, Gustave Roussy Cancer Center, Villejuif, France.
authors.forename: B
authors.initials: B
authors.lastname: Cheaib
authors.affiliation: INSERM U981 Gynaecological Tumours, Gustave Roussy Cancer Center, Villejuif.|Departments of Biopathology, Gustave Roussy, Villejuif, France.
authors.forename: J
authors.initials: J
authors.lastname: Adam
authors.affiliation: INSERM U981 Gynaecological Tumours, Gustave Roussy Cancer Center, Villejuif.|Faculty of Sciences, University Paris-Sud, Orsay.|Oncology, Gustave Roussy Cancer Center, Villejuif, France.
authors.forename: A F
authors.initials: AF
authors.lastname: Leary
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D000077216:Carcinoma, Ovarian Epithelial; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011379:Prognosis
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human
keywords: PD-L1; epithelial ovarian cancer; neoadjuvant chemotherapy; tumour infiltrating lymphocytes