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

A B S T R A C T PurposeMounting 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). Patients and MethodsUsing tissue microarray and immunohistochemistry, we investigated eight types of tumorinfiltrating 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). ResultsAlthough a high density of stromal forkhead box P3 (FoxP3) -positive cells was associated with shorter recurrence-free probability (RFP; P ϭ .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 ϭ .004). High expression of tumor interleukin-12 receptor ␤2 (IL-12R␤2) was associated with better outcome (5-year RFP, 90% for high v 80% for low expression; P ϭ .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 ϭ .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 Յ 2 cm. ConclusionOur 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.

The tumor immune microenvironment in octogenarians with stage I non-small cell lung cancer

“…We [20][21][22][23] and others [15][16][17]19 have shown the prognostic significance of the tumor immune microenvironment in solid malignancies. To the best of our knowledge, there have been no published studies on the association between tumor-infiltrating immune cells and elderly patients in either NSCLC or other solid malignancies.…”

“…20 In brief, the slide with the most severe inflammatory reaction was chosen for each tumor. Then, 2 to 6 representative TMA cores that were obtained from each tumor nest with the most abundant inflammatory reaction (0.6 mm) were made for further immunohistochemical analysis.…”

“…Under high-power field (magnification, 200x), each core was semi-quantitatively scored for degree of immune cell infiltration in the tumor nest, as previously described. 20 Scores for each core were averaged to give 1 score per patient, as previously reported. 20,41 Statistical analysis Patients were classified into 3 categories based on their age at time of surgical resection for lung cancer: 65 years of age, 66-79 years of age, and 80 years of age.…”

“…20 Scores for each core were averaged to give 1 score per patient, as previously reported. 20,41 Statistical analysis Patients were classified into 3 categories based on their age at time of surgical resection for lung cancer: 65 years of age, 66-79 years of age, and 80 years of age. Associations between clinical and immune variables and these age categories were analyzed using the Cochran-Armitage trend test.…”

“…13,14 The immune microenvironment is increasingly being recognized as a strong prognostic factor of solid malignancies, including colorectal, [15][16][17] ovarian, 18 and breast cancers. 19 In a previously published study, 20 we reported the biologic and prognostic significance of the tumor immune microenvironment using a large-scale test and validation cohort of Stage I lung adenocarcinoma (ADC) patients. In this study, among patients with high densities of forkhead box P3 (FoxP3 C ) regulatory T cells, those with high densities of CD3 C T cells had better clinical outcomes than those with low densities of CD3 C T cells.…”