Cytotoxicity of Activated Natural Killer Cells and Expression of Adhesion Molecules in Small-cell Lung Cancer

Background/Aim: Although small-cell lung cancer (SCLC) is sensitive to anticancer agents, most patients with SCLC experience relapse and die within two years. Here, we examined the relationship between natural killer (NK) cells and adhesion molecules on SCLC cell lines. Materials and Methods: The expression levels of HLA class I, β2-microglobulin, Fas/Apo-1 receptor (FAS) and adhesion molecules on SCLC cell lines were examined by flow cytometry. The cytotoxicity of activated NK cells from SCLC patients was examined using 51 Cr-release assay. Results: HLA class I antigen and β2-microglobulin expression levels in SCLC cell lines were lower than those in healthy volunteers. SCLC cell lines were susceptible to lysis by activated NK cells but this showed no correlation with expression levels of adhesion molecules. Conclusion: Target cell susceptibility to activated NK cells from five SCLC patients correlated with survival benefit; target cell susceptibility to activated NK cells may be a surrogate marker of outcome for patients with SCLC. Lung cancer is the leading cause of cancer mortality in Japan and the majority of industrialized countries. While its incidence has decreased in the US, lung cancer is still increasing in many developing countries (1). Small-cell lung cancer (SCLC) is one of the solid tumors most sensitive to anticancer agents. Generally, platinum-based chemotherapy including etoposide or irinotecan is the mainstay of first-line treatment for SCLC. The objective response rate for SCLC with recent chemotherapy combinations exceeds 50%, even in patients with extensive disease, in Western countries (2). Despite high initial response rates, most patients eventually experience disease relapse. Except for topotecan and amrubicin, few treatment options remain after relapse (3, 4). Clinical trials of high-dose chemotherapy and autologous hematopoietic stem cell transplantation (AHSCT) showed that progression-free survival could be improved in patients with limited SCLC and in a few patients with extensive SCLC about a decade ago (5, 6); however, these positive results obtained in phase II clinical trials with high-dose chemotherapy were not confirmed in large-scale phase III trials. The SCLC chemotherapy status has not changed for 15 years, despite marked progress in molecular targeted therapy based on oncogenic driver mutation in non-SCLC (7). Accordingly, new approaches to improve SCLC treatment outcomes are needed. A meta-analysis of published randomized clinical trials involving maintenance therapy following systemic chemotherapy using cytokines showed no survival advantage (8). These results suggest that maintenance and/or the consolidation approach using interferons and other biological agents failed to improve SCLC outcomes. In an effort to investigate the possibility of an immunological approach using natural killer (NK) cells, we performed experiments to clarify the relationship between NK cell activity and adhesion molecules on SCLC cell lines.