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

Jingya Guo, Yong Liang, Diyuan Xue, Jiao Shen, Yueqi Cai, Jiankun Zhu, Yang Xin Fu, Hua Peng

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1190-1198
Number of pages9
JournalCell Research
Issue number11
StatePublished - Nov 2021
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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