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
- 1 February 2013
- journal article
- research article
- Published by American Society of Clinical Oncology (ASCO) in Journal of Clinical Oncology
- Vol. 31 (4), 490-498
- https://doi.org/10.1200/jco.2012.45.2052
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
This publication has 34 references indexed in Scilit:
- Regulatory T-cell Modulation Using Cyclophosphamide in Vaccine Approaches: A Current PerspectiveCancer Research, 2012
- Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast CancerJournal of Clinical Oncology, 2011
- Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I casesLaboratory Investigation, 2011
- Combination CTLA-4 Blockade and 4-1BB Activation Enhances Tumor Rejection by Increasing T-Cell Infiltration, Proliferation, and Cytokine ProductionPLOS ONE, 2011
- International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung AdenocarcinomaJournal of Thoracic Oncology, 2011
- Histopathologic-Based Prognostic Factors of Colorectal Cancers Are Associated With the State of the Local Immune ReactionJournal of Clinical Oncology, 2011
- Tumor-Infiltrating Foxp3+ Regulatory T Cells are Correlated with Cyclooxygenase-2 Expression and are Associated with Recurrence in Resected Non-small Cell Lung CancerJournal of Thoracic Oncology, 2010
- Overexpression of Phospho-eIF4E Is Associated with Survival through AKT Pathway in Non–Small Cell Lung CancerClinical Cancer Research, 2010
- In Situ Cytotoxic and Memory T Cells Predict Outcome in Patients With Early-Stage Colorectal CancerJournal of Clinical Oncology, 2009
- New insights into the regulation of T cells by γc family cytokinesNature Reviews Immunology, 2009