IL-15 Superagonist SHR-1501 Enhances Immune Responses in Lung Cancer by Modulating Tumor Microenvironment.

BACKGROUND: Interleukin-15 (IL-15) is a pleiotropic cytokine recognized as a promising therapeutic agent in cancer immunotherapy. IL-15 superagonists have shown efficacy across various cancers, yet their effects in lung cancer immunotherapy remain underexplored. METHODS: This study evaluated the antitumor effects of SHR-1501 through intratumoral injection in two murine lung cancer models: Lewis lung carcinoma (LLC) and Kras G12D/p53-/- (KP). We employed flow cytometry to assess immune cell populations in the tumor microenvironment (TME) and systemic circulation. Immunohistochemistry (IHC) was used to analyze TME changes in tumor tissues, while single-cell RNA sequencing provided insights into TME modulation following SHR-1501 treatment. Additionally, we assessed the synergistic potential of combining SHR-1501 with PD-1 monoclonal antibody (mAb) therapy and explored the abscopal effect of SHR-1501. RESULTS: SHR-1501 significantly inhibited tumor growth in both KP and LLC models at 5 μg and 15 μg doses (p = 0.0022 and p = 0.0002, respectively, for KP; p = 0.0508 and p = 0.0131, respectively, for LLC). Flow cytometry revealed increased infiltration of CD8+ T cells, effector memory CD8+ T cells (TEM), and natural killer (NK) cells in the TME. SHR-1501 also enhanced systemic immune responses, increasing CD8+ T cells and TEM populations in peripheral blood and spleen, with an early NK cell elevation on day 7 post-treatment. Single-cell analysis indicated that SHR-1501 promoted the activity of macrophages, increasing M1 macrophage proportions. Moreover, SHR-1501 enhanced the antitumor immune response by promoting pro-inflammatory changes across multiple cell types within the TME, including neutrophils, fibroblasts, and endothelial cells. When combined with PD-1mAb, SHR-1501 exhibited potent synergistic antitumor effects. The combination therapy significantly prolonged overall survival with no significant toxicity observed. Furthermore, SHR-1501 may have the ability to induce an abscopal effect. CONCLUSION: SHR-1501 demonstrated potent antitumor activity, especially when combined with PD-1 mAb. Its mechanism likely involves promoting CD8+ T cell and NK cell infiltration and enhancing M1 macrophage activity. These findings provide evidence for further clinical trials exploring SHR-1501 in nonsmall cell lung cancer (NSCLC) therapy.