title: Correlation of metabolic information on FDG-PET with tissue expression of immune markers in patients with non-small cell lung cancer (NSCLC) who are candidates for upfront surgery.
abstract: OBJECTIVE
  Eliciting antitumor T-cell response by targeting the PD-1/PD-L1 axis with checkpoint inhibitors has emerged as a novel therapeutic strategy in non-small cell lung cancer (NSCLC). The identification of predictors for sensitivity or resistance to these agents is, therefore, needed. Herein, we investigate the correlation of metabolic information on FDG-PET with tissue expression of immune-checkpoints and other markers of tumor-related immunity in resected NSCLC patients.
  
  
  METHODS
  All patients referred to our institution for upfront surgical resection of NSCLC, who were investigated with FDG-PET prior to surgery, were consecutively included in the study. From January 2010 to May 2014, 55 patients (stage IA-IIIB; M:F = 42:13; mean age 68.9 years) were investigated. Sampled surgical tumor specimens were analyzed by immunohistochemistry (IHC) for CD68-TAMs (tumor-associated macrophages), CD8-TILs (tumor infiltrating lymphocytes), PD-1-TILs, and PD-L1 tumor expression. Immunoreactivity was evaluated, and scores were compared with imaging findings. FDG-PET images were analyzed to define semi-quantitative parameters: SUVmax and SUVmean. Metabolic information on FDG-PET was correlated with tissue markers expression and disease-free survival (DFS) considering a median follow-up of 16.2 months.
  
  
  RESULTS
  Thirty-six adenocarcinomas (ADC), 18 squamous cell carcinomas (SCC), and one sarcomatoid carcinoma were analyzed. All tumors resulted positive at FDG-PET: median SUVmax 11.3 (range: 2.3-32.5) and SUVmean 6.4 (range: 1.5-13) both resulted significantly higher in SCC compared to other NSCLC histotypes (p = 0.007 and 0.048, respectively). IHC demonstrated a median immunoreactive surface covered by CD68-TAMs of 5.41 % (range: 0.84-14.01 %), CD8-TILs of 2.9 % (range: 0.11-11.92 %), PD-1 of 0.65 % (range: 0.02-5.87 %), and PD-L1 of 0.7 % (range: 0.03-10.29 %). We found a statistically significant correlation between SUVmax and SUVmean with the expression of CD8 TILs (rho = 0.31; p = 0.027) and PD-1 (rho = 0.33; p = 0.017 and rho = 0.36; p = 0.009, respectively). The other tissue markers correlated as follows: CD8 TILs and PD-1 (rho = 0.45; p = 0.001), CD8 TILs and PD-L1 (rho = 0.41; p = 0.003), CD68-TAMs and PD-L1 (rho = 0.30; p = 0.027), PD-1 and PD-L1 (rho = 0.26; p = 0.059). With respect to patients' outcome, SUVmax, SUVmean, and disease stage showed a statistically significant correlation with DFS (p = 0.002, 0.004, and <0.001, respectively).
  
  
  CONCLUSIONS
  The present study shows a direct association between metabolic parameters on FDG-PET and the expression of tumor-related immunity markers, suggesting a potential role for FDG-PET to characterize the tumor microenvironment and select NSCLC patients candidate to checkpoint inhibitors.
authors.affiliation: Nuclear Medicine Department, Humanitas Clinical and Research Hospital, Via Manzoni 56, 20089, Rozzano, MI, Italy. egesta.lopci@gmail.com.
authors.forename: Egesta
authors.initials: E
authors.lastname: Lopci
authors.affiliation: Oncology, Humanitas Clinical and Research Hospital, 20089, Rozzano, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Toschi
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Hospital, 20089, Rozzano, Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Grizzi
authors.affiliation: Department of Pathology, Humanitas Clinical and Research Hospital, 20089, Rozzano, Milan, Italy.
authors.forename: Daoud
authors.initials: D
authors.lastname: Rahal
authors.affiliation: Nuclear Medicine Department, Humanitas Clinical and Research Hospital, Via Manzoni 56, 20089, Rozzano, MI, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Olivari
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Hospital, 20089, Rozzano, Milan, Italy.
authors.forename: Giovanni Francesco
authors.initials: GF
authors.lastname: Castino
authors.affiliation: Oncology, Humanitas Clinical and Research Hospital, 20089, Rozzano, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Marchetti
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Hospital, 20089, Rozzano, Milan, Italy.
authors.forename: Nina
authors.initials: N
authors.lastname: Cortese
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Hospital, 20089, Rozzano, Milan, Italy.
authors.forename: Dorina
authors.initials: D
authors.lastname: Qehajaj
authors.affiliation: Oncology, Humanitas Clinical and Research Hospital, 20089, Rozzano, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pistillo
authors.affiliation: Thoracic Surgery, Humanitas Clinical and Research Hospital, 20089, Rozzano, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Alloisio
authors.affiliation: Department of Pathology, Humanitas Clinical and Research Hospital, 20089, Rozzano, Milan, Italy.|Humanitas University, Rozzano, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Roncalli
authors.affiliation: Humanitas University, Rozzano, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Allavena
authors.affiliation: Oncology, Humanitas Clinical and Research Hospital, 20089, Rozzano, Milan, Italy.|Humanitas University, Rozzano, Milan, Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Santoro
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Hospital, 20089, Rozzano, Milan, Italy.|Department of Medical Biotechnologies and Translational Medicine, University of Milan, 20122, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Marchesi
authors.affiliation: Nuclear Medicine Department, Humanitas Clinical and Research Hospital, Via Manzoni 56, 20089, Rozzano, MI, Italy.|Humanitas University, Rozzano, Milan, Italy.
authors.forename: Arturo
authors.initials: A
authors.lastname: Chiti
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000276:immunology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging / Q000276:immunology* / Q000601:surgery; D016207:Cytokines / Q000276:immunology; D018572:Disease-Free Survival; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000276:immunology*; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology*; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000276:immunology* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D057054:Molecular Imaging / Q000379:methods; D049268:Positron-Emission Tomography / Q000379:methods*; D011300:Preoperative Care / Q000379:methods; D019275:Radiopharmaceuticals; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013223:Statistics as Topic
chemical_list: D014408:Biomarkers, Tumor; D016207:Cytokines; D007155:Immunologic Factors; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18
keywords: FDG-PET; Immunometabolism; NSCLC; PD-L1; TAMs; TILs; Tumor-related immunity