Tumor-Infiltrating Lymphocytes and Overall Survival in Surgically Resected Stage II and III Non–Small Cell Lung Cancer

Abstract

Improved response rates and survival in advanced lung cancer patients treated with immunotherapy stimulated an interest in tumor microenvironment and its role in predicting outcome. We evaluated the influence of tumor microenvironment on overall survival (OS) in surgical resected stage II and III non–small cell lung cancers. Pathologic specimens of 79 stage II and 50 stage III surgically resected lung cancers were analyzed for programmed cell death ligand 1 (PD-L1) expression and different subclasses of lymphocytes (CD3, CD4, CD8, CD57, CD45RO, FOXP3, and CD68) utilizing immunohistochemistry and image analysis. Other tested variables included tumor size, T and N stage, age, and adjuvant therapy. Recursive partitioning, univariable, multivariable, and Kaplan-Meier analyses were used to identify predictors of survival. In pathologic stage II lung cancers, recursive partitioning and multivariable analysis identified the concentration of CD8 cells (cytotoxic T cells) > 2172 per mm2 (P=.004, HR 0.44), CD45RO (memory T cells) > 840 mm2 (P=.011, HR 0.29), and CD57 (effector T cells) > 586 mm2 (0.08, HR 0.46) in the peritumoral stroma to be associated with favorable survival. Interestingly, CD45RO > 1891 mm2(P=.000, HR 12.4) inside the tumor negatively influenced survival. In pathologic stage III lung cancers, intratumoral concentration of CD8 (cytotoxic T cells) > 373 mm2 (P=.001, HR 0.097) and FOXP3 (regulatory T cells) > 559mm2 (P=.081, HR 0.16) were independently associated with favorable survival. Five-year survival for patients with CD8 > 373mm2 was 47%; there were no survivors in the group with CD8 < 373mm2. PD-L1 expression at any percentage level was not predictive of survival in either stage II or stage III patients. The interaction between immune cells within the tumor and surrounding stroma is complex and not fully understood. The association between immune cells and survival requires validation, but also suggests that enhancing the immune system anti-tumor response prior to surgical resection may potentially improve outcomes in locoregionally advanced NSCLC.