Interleukin-15; a potential factor in lung cancer establishment and progression of lung cancer

Background: Interleukin-15 (IL-15) is a potent pro-inflammatory cytokine, that plays a major role in stimulating immune effector cells following microbial and viral infection. IL-15 exhibits broad activity and induces the differentiation and proliferation of T, B and natural killer (NK) cells. IL-15 is primarily expressed by antigen presenting cells; however, in areas where there are high microbial loads, such as the lungs and colon, epithelial cells may also express IL-15 and its receptor (IL-15Ra). The expression of IL-15 and IL-15Ra by the lung epithelium facilitates immune responses by inducing local proliferation of NK and CD8+ T-cells in response to infection. Here we determine the status of IL-15 and IL-15Ra on lung cancers and assess their ability to stimulate the proliferation of these immune cells. Methods: Western blotting, ELISA and qPCR were used to determine the expression of IL-15 and IL-15Rα in 6 human lung cancer cell lines and 1 normal human bronchial epithelial cell (HBEC) line. Further, mRNA from 146 primary lung cancers of all stages and tissues from 45 normal lungs were examined by multiplex qPCR for the expression of IL-15 and IL-15Rα. NK and T-cell proliferation assays were performed to determine the effects of IL-15 expression by the cell lines on these immune cells. Results: IL-15 expression by lung cancer cell lines was significantly reduced compared to the HBEC cell line. Similar results were seen when we examined the expression of IL-15 in primary tumors, with lung cancer expressing less IL-15 than normal lung (P<0.001). When we compared IL-15 expression between stages, we found that increased stage correlated with a decrease in IL-15 expression with normal lung> stage I> stage II> stage III> stage IV. In contrast, IL-15Rα expression levels in the tumor samples were found to be largely unchanged across stage, P=0.417. Decreases in IL-15 with increasing stage may represent one mechanism in which lung cancers limit the immune response directed at the tumor and may aid in metastatic progression. In order to assess the immune effects of a reduction in IL-15 expression, we examined the ability of the lung cancer cell lines and HBEC to induce the proliferation of NK and T-cells following co-incubation. We found that the lung cancer cell lines significantly inhibited the proliferation of either NK or T-cells compared to HBEC. Conclusion: Pro-inflammatory cytokines such as IL-15 are important for the induction of lung immunity. Decreases in IL-15 expression may reduce immune responses thereby aiding in the escape of lung cancer from immune detection and the dissemination of tumor. The differential expression of IL-15 across lung cancer stages and retention of IL-15Rα expression may make lung cancer a target for IL-15-based treatments and opens the potential for IL-15 to be used as a predictive biomarker in early stage patients.