Panoply™ Human IL15 Over-expressing Stable Cell Line

IL-15 plays a crucial role in enhancing NK cell- and T cell-mediated anti-tumor immune responses; however, the direct effects of IL-15 on tumor cells have not been fully elucidated. Here, researchers investigated the effects of IL-15 on lung adenocarcinoma cells. The results showed that endogenous IL-15 within cancer cells promoted cell motility and migration in vitro and tumor metastasis in vivo by activating the AKT-mTORC1 pathway; in contrast, exogenous IL-15 inhibited cell motility and migration by suppressing the RhoA-MLC2 axis. Mechanistic analysis revealed that these effects mediated by intracellular and extracellular IL-15 were dependent on the expression of IL-15Rα on the tumor cell surface. Further analysis showed that the complex formed by intracellular IL-15 and IL-15Rα lacked the IL-2/IL-15Rβ and IL-2Rγ subunits, whereas exogenous IL-15 formed a complex containing IL-15Rα, IL-2/IL-15Rβ, and IL-2Rγ subunits upon interacting with tumor cells. This suggests that the distinct effects of intracellular and extracellular IL-15 on tumor cells may stem from differences in how they bind to IL-15 receptors. Using a Lewis lung carcinoma (LLC) metastasis model, researchers found that although IL-15 overexpression promoted lung metastasis of LLC cells, IL-15-overexpressing LLC tumors were more sensitive to anti-PD-L1 therapy compared to wild-type LLC tumors; this enhanced sensitivity was attributed to an augmented anti-tumor immune response, specifically characterized by increased CD8+ T cell infiltration. In summary, endogenous IL-15 in cancer cells acts as a "double-edged sword" during tumor progression. Furthermore, high-level IL-15 expression by tumor cells may enhance the tumor's responsiveness to immunotherapy.

To investigate how endogenous IL-15 influences cancer cell migration and invasion, researchers examined the signaling cascades mediated by endogenous IL-15 in cancer cells. Loss of IL-15 expression in A549 and PC9 cells resulted in significantly reduced AKT phosphorylation and inhibited mTORC1 activation (indicated by decreased phosphorylation of p70S6K and S6); conversely, AKT phosphorylation and mTORC1 activity were enhanced in A549 and PC9 cells overexpressing IL-15 (Figure 1A). Subsequently, to determine whether the AKT-mTORC1 pathway is involved in IL-15-induced tumor cell migration, researchers used the inhibitors LY294002 and rapamycin to block AKT and mTORC1 activity, respectively. The results showed that treatment with LY294002 (Figure 1B) or rapamycin (Figure 1C) significantly impaired the migratory capacity of IL-15-overexpressing tumor cells. Furthermore, compared with wild-type A549 and PC9 cells, IL-15-overexpressing A549 and PC9 cells exhibited higher Cdc42 activity (Figure 1D). Cdc42 is known to regulate the formation of filopodia-actin bundle-containing protrusions at the cell periphery. Next, the researchers investigated whether IL-15 induces morphological changes in tumor cells through cytoskeletal remodeling. Knockdown of IL-15 significantly reduced the number of filopodia in A549 and PC9 cells, whereas IL-15 overexpression promoted filopodia formation (Figure 1E and F). Moreover, inhibiting AKT and mTORC1 activity in IL-15-overexpressing cells attenuated Cdc42 activity (Figure 1G) and suppressed filopodia formation (Figure 1H and I). These data indicate that endogenous IL-15 in cancer cells activates the AKT-mTORC1 pathway, thereby enhancing Cdc42 activity and inducing cytoskeletal remodeling, which promotes cell migration and invasion.

Figure 1. Cancer cell-intrinsic IL-15 activates the AKT-mTORC1-Cdc42 axis, leading to an increase in filopodium formation. (Hu S, et al., 2024)