Effects of an engineered IL-2 partial agonist on natural killer cell anti-tumor activity 3729

Description Natural killer (NK) cell activity is regulated by cytokines and activating receptors expressed on the cells. Optimizing NK cell actions for cancer immunotherapy requires a balance between their proliferative activity and effector function in response to cytokines. H9T is an IL-2 variant that enhances the anti-tumor activity of CD8+ T cells in adoptive immunotherapy, maintaining a stem-like phenotype associated with reduced functional exhaustion. Here, we investigated the ability of H9T to regulate the function of NK cells. Unlike IL-2, H9T did not induce NK cell proliferation but could do so in combination with activating receptor signaling. NK cells have a distinct transcriptional response to H9T compared to either IL-2 or H9, marked by higher expression of activating receptors and chemokines and the loss of effector or exhaustion markers. H9T enhanced expression of TRAIL and correspondingly enhanced NK cell-mediated killing of RMA-S lymphomas in vitro. Moreover, H9T treatment of mice with RMA-S tumors led to increased tumor infiltration by NK cells, and these cells had increased expression of markers of “stemness” and decreased expression of exhaustion markers. These results suggest that H9T treatment favors the production of NK cells with a distinctive array of proteins, allowing better migration into the tumor microenvironment and more efficient target lysis. Further analyses will elucidate ways to enhance the role of NK cells in anti-tumor immunotherapy.