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

Abstract

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-3-CD8+ 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.

• Authors: Jingya Guo, Yong Liang, Diyuan Xue, Jiao Shen, Yueqi Cai, Jiankun Zhu, Yang-Xin Fu, Hua Peng
• Journal: Cell research (Cell Res) Vol. 31 Issue 11 Pg. 1190-1198 (11 2021) ISSN: 1748-7838 [Electronic] England
• PMID: 34376814 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Center for Excellence in Molecular Cell Science, CAS.

Chemical References

• Cytokines
• Interleukin-15

Topics

• Animals
• CD8-Positive T-Lymphocytes
• Cytokines
• Immunotherapy
• Interleukin-15
• Mice
• Neoplasms (drug therapy)
• Tumor Microenvironment