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Tumor-conditional IL-15 pro-cytokine reactivates anti-tumor immunity with limited toxicity


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-IL-15 has the extracellular domain of IL-15Rβ fused to the N-terminus of sIL-15-Fc through a tumor-enriched Matrix Metalloproteinase (MMP) cleavable peptide linker to block its activity. Unlike sIL-15-Fc, pro-IL-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-IL-15 depends on intratumoral CD8+ T cells and IFN-γ. Pro-IL-15 increases the stem-like TCF1+Tim-3CD8+ T cells within tumor tissue and helps overcome immune checkpoint blockade (ICB) resistance. Moreover, pro-IL-15 synergizes with current tyrosine kinase inhibitor (TKI) targeted-therapy in a poorly inflamed TUBO tumor model, suggesting that pro-IL-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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Fig. 1: Poor tumor control and severe toxicity after systemic delivery of sIL-15-Fc.
Fig. 2: Engineering a tumor-conditional pro-IL-15.
Fig. 3: Pro-IL-15 avoids peripheral NK expansion mediated toxicity.
Fig. 4: Pro-IL-15 preserves anti-tumor activity.
Fig. 5: Pro-IL-15 activates and expands pre-existing CD8+ T cells for tumor control.
Fig. 6: Pro-IL-15 overcomes the checkpoint blockade resistance to control advanced tumors.
Fig. 7: TKI therapy can synergize with pro-IL-15 therapy to control cold tumors.


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We thank Yang Wang for her technical assistance and providing reagents. We thank Benjamin Moon for the excellent editing. We thank Hui Su and Sai Yang for technical assistance in IBP. This work was partly supported by the funding from the National Science Foundation of China (No. 81803086) to Y. Liang.

Author information




J.G., Y.L., H.P., and Y.-X.F. conceptualized the project and designed experiments. J.G. and Y.L. performed experiments. J.G. and Y.L. analyzed data. J.G., Y.L., H.P., and Y.-X.F. contributed to manuscript preparation. D.X., J.S., Y.C., and J.Z. provided technical or material supports. Y.L., H.P., and Y.-X.F. supervised the project.

Corresponding authors

Correspondence to Yong Liang, Yang-Xin Fu or Hua Peng.

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The authors declare no competing interests.

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Guo, J., Liang, Y., Xue, D. et al. Tumor-conditional IL-15 pro-cytokine reactivates anti-tumor immunity with limited toxicity. Cell Res (2021).

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