Tumor cellular proliferation is associated with enhanced immune checkpoint expression in stage I non–small cell lung cancer

Ki67 is a marker for tumor proliferative activity and is known to have prognostic significance in multiple solid malignancies. We sought to characterize the relationships among Ki67 expression, immune cell infiltration, and immune checkpoint expression in patients with resected non–small cell lung cancer. Specimens of patients undergoing resection of stage I to III non–small cell lung cancer (1997-2012) were analyzed using tissue microarrays. Proliferative index was quantified as the percentage of malignant cells expressing Ki67. Checkpoints expressed on malignant cells (programmed death ligand 1, B7H3, B7H4, indoleamine 2,3-dioxygenase 1) and lymphocytes (T-cell immunoglobulin and mucin-domain containing 3, V-domain suppressor of T-cell activation, tumor necrosis factor receptor superfamily member 4, lymphocyte activation gene 3, inducible T-cell co-stimulator) were analyzed in intratumoral and stromal compartments, respectively. Immune cell densities were quantified in intratumoral and peritumoral compartments in a representative subset. A total of 190 patients met inclusion criteria. Higher Ki67 expression was noted in squamous cell carcinoma (median 31.4% positive malignant cells vs 15.2% adenocarcinoma, P