title: Clinical impact of immune microenvironment in stage I lung adenocarcinoma: tumor interleukin-12 receptor β2 (IL-12Rβ2), IL-7R, and stromal FoxP3/CD3 ratio are independent predictors of recurrence.
abstract: OBJECTIVE
  Mounting evidence suggests that tumor-infiltrating immune cells have prognostic value for patients with solid organ malignancies. Our aim was to investigate the prognostic significance of the immune microenvironment in patients with stage I lung adenocarcinoma (ADC).
  
  
  METHODS
  Using tissue microarray and immunohistochemistry, we investigated eight types of tumor-infiltrating immune cells in the tumor nest and tumor-associated stroma as well as tumor expression of five cytokines in a uniform cohort of 956 patients with stage I lung ADC (478 each in training and validation cohorts).
  
  
  RESULTS
  Although a high density of stromal forkhead box P3 (FoxP3) -positive cells was associated with shorter recurrence-free probability (RFP; P = .043), the relative proportion of stromal FoxP3 to CD3 was a stronger predictor of recurrence (5-year RFP, 85% for high v 77% for low ratio; P = .004). High expression of tumor interleukin-12 receptor β2 (IL-12Rβ2) was associated with better outcome (5-year RFP, 90% for high v 80% for low expression; P = .026), whereas high expression of tumor IL-7R was associated with worse outcome (5-year RFP, 76% for high v 86% for low expression; P = .001). In multivariate analysis, these immune markers were independently associated with recurrence. Although IL-7R remained significant for poor overall survival, all the markers remained prognostic for recurrence in patients with stages IA and IB disease as well as for patients with tumors ≤ 2 cm.
  
  
  CONCLUSIONS
  Our investigation confirms the biologic and prognostic significance of the tumor immune microenvironment for patients with stage I lung ADC and provides support for its use to stratify clinical outcome and immunotherapeutic interventions.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Kei
authors.initials: K
authors.lastname: Suzuki
authors.forename: Kyuichi
authors.initials: K
authors.lastname: Kadota
authors.forename: Camelia S
authors.initials: CS
authors.lastname: Sima
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Nitadori
authors.forename: Valerie W
authors.initials: VW
authors.lastname: Rusch
authors.forename: William D
authors.initials: WD
authors.lastname: Travis
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
authors.forename: Prasad S
authors.initials: PS
authors.lastname: Adusumilli
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D017252:CD3 Complex / Q000032:analysis*; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D008207:Lymphatic Metastasis; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000276:immunology*; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D053707:Receptors, Interleukin-12 / Q000032:analysis*; D020395:Receptors, Interleukin-7 / Q000032:analysis*; D018570:Risk Assessment; D012307:Risk Factors; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D017252:CD3 Complex; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508439:IL12RB2 protein, human; D053707:Receptors, Interleukin-12; D020395:Receptors, Interleukin-7