Biology of Human Tumors Stromal CD8þ T-cell Density—A Promising Supplement to TNM Staging in Non–Small Cell Lung Cancer

Purpose: Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates, which appears to be superior to the tumor–node–metastasis (TNM) classification in colorectal cancer. In non–small cell lung cancer (NSCLC), no immunoscore has been established, but in situ tumor immunology is recognized as highly important. We have previously evaluated the prognostic impact of several immunological markers in NSCLC, yielding the density of stromal CD8þ tumor-infiltrating lymphocytes (TIL) as the most promising candidate. Hence, we validate the impact of stromal CD8þ TIL density as an immunoscore in NSCLC. Experimental Design: The prognostic impact of stromal CD8þ TILs was evaluated in four different cohorts from Norway and Denmark consisting of 797 stage I–IIIA NSCLC patients. The Tromso cohort (n1⁄4 155) was used as training set, and the results were further validated in the cohorts from Bodo (n 1⁄4 169), Oslo (n 1⁄4 295), and Denmark (n 1⁄4 178). Tissue microarrays and clinical routine CD8 staining were used for all cohorts. Results: Stromal CD8þ TIL density was an independent prognostic factor in the total material (n 1⁄4 797) regardless of the endpoint: disease-free survival (P < 0.001), disease-specific survival (P < 0.001), or overall survival (P < 0.001). Subgroup analyses revealed significant prognostic impact of stromal CD8þ TIL density within each pathologic stage (pStage). In multivariate analysis, stromal CD8þ TIL density and pStage were independent prognostic variables. Conclusions: Stromal CD8þ TIL density has independent prognostic impact in resected NSCLC, adds prognostic impact within each pStage, and is a good candidate marker for establishing a TNM-Immunoscore. Clin Cancer Res; 21(11);