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 Journal Article


Authors: Suzuki, K.; Kadota, K.; Sima, C. S.; Nitadori, J.; Rusch, V. W.; Travis, W. D.; Sadelain, M.; Adusumilli, P. S.
Article 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: 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). 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). 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. 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.
Keywords: immunohistochemistry; adult; aged; aged, 80 and over; middle aged; mortality; cancer staging; lymph node metastasis; lymphatic metastasis; neoplasm staging; adenocarcinoma; cd3 antigen; tumor associated leukocyte; antigens, cd3; forkhead transcription factors; lymphocytes, tumor-infiltrating; metabolism; neoplasm recurrence, local; lung neoplasms; tumor markers, biological; risk factors; pathology; tumor marker; risk factor; risk assessment; cancer invasion; lung tumor; immunology; tumor recurrence; predictive value of tests; tissue array analysis; multivariate analysis; neoplasm invasiveness; tissue microarray; kaplan meier method; forkhead transcription factor; predictive value; foxp3 protein, human; receptors, interleukin-7; kaplan-meier estimate; interleukin 7 receptor; interleukin 12 receptor; receptors, interleukin-12; il12rb2 protein, human
Journal Title: Journal of Clinical Oncology
Volume: 31
Issue: 4
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2013-02-01
Start Page: 490
End Page: 498
Language: English
DOI: 10.1200/jco.2012.45.2052
PUBMED: 23269987
PROVIDER: scopus
PMCID: PMC3731922
DOI/URL:
Notes: --- - "Export Date: 1 April 2013" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Camelia S Sima
    204 Sima
  2. Valerie W Rusch
    651 Rusch
  3. William D Travis
    548 Travis
  4. Kei Suzuki
    28 Suzuki
  5. Michel W J Sadelain
    452 Sadelain
  6. Kyuichi Kadota
    82 Kadota