【摘 要】
：
IL-15 is a promising cytokine to expand NK and CD8+T cells for cancer immunotherapy,but its application is limited by dose-limiting,on-target off-tumor toxicity.Here,we have developed a next-generation IL-15 that is activated inside the tumor microenviron
【机 构】
：
Chinese Academy of Sciences Key Laboratory of Infection and Immunity,Institute of Biophysics,Chinese
论文部分内容阅读
IL-15 is a promising cytokine to expand NK and CD8+T cells for cancer immunotherapy,but its application is limited by dose-limiting,on-target off-tumor toxicity.Here,we have developed a next-generation IL-15 that is activated inside the tumor microenvironment (TME).This pro-lL-15 has the extracellular domain of IL-15Rβ fused to the N-terminus of slL-15-Fc through a tumor-enriched Matrix Metalloproteinase (MMP) cleavable peptide linker to block its activity.Unlike slL-15-Fc,pro-lL-15 does not activate the peripheral expansion of NK cells and T cells,thus reducing systemic toxicity,but it still preserves efficient anti-tumor abilities.In various mouse tumors,the anti-tumor effect of pro-lL-15 depends on intratumoral CD8+T cells and IFN-y.Pro-lL-15 increases the stem-like TCF1+Tim-3-CD8+ T cells within tumor tissue and helps overcome immune checkpoint blockade (ICB)resistance.Moreover,pro-lL-15 synergizes with current tyrosine kinase inhibitor (TKI) targeted-therapy in a poorly inflamed TUBO tumor model,suggesting that pro-lL-15 helps overcome targeted-therapy resistance.Our results demonstrate a next-generation IL-15 cytokine that can stimulate potent anti-tumor activity without severe toxicity.
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