An IL-15 fusion with albumin-binding domain boosts immunotherapy therapy in glioblastoma via FGF-2 competition regulating FGFR1/2.

Given the high heterogeneity and immunosuppressive nature of glioblastoma (GBM), standard monotherapies such as chemotherapy, radiotherapy, and immunotherapy show limited efficacy. Therefore, urgent combined treatment strategies-like immunostimulatory recombinant proteins-are needed. Compared to interleukin-2 (IL-2), IL-15 is a promising agent without the drawback of activation-induced cell death (AICD). We engineered a recombinant human IL-15 fused with an albumin-binding domain (hIL-15-ABD) to prolong IL-15's half-life and enhance blood-brain barrier penetration. We evaluated whether hIL-15-ABD could boost the efficacy of immune checkpoint inhibitors (ICIs) in a GBM model. Our findings indicate that hIL-15-ABD significantly improves the anti-GBM effects of anti-PD-L1 and anti-PD-1 therapies by increasing M1 macrophage populations, activating cytotoxic T cells, and promoting natural killer cell responses in an orthotopic GBM model. hIL-15-ABD enhanced the efficacy of both anti-PD-L1 (10 F.9G2) in C57BL/6 mice and anti-PD-1 (nivolumab) in a GL261 model using humanized PD1+/+ mice. Notably, hIL-15-ABD not only boosts immunostimulation but also reduces the proportions of immunosuppressive cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), in the tumor microenvironment. Additionally, hIL-15-ABD appears to target FGF-2 and its receptors, inactivating the FGF-2/FGFR1/2 pathways. In summary, hIL-15-ABD shows potential as an immunostimulatory agent for ICIs in GBM treatment.