Tumor-conditional IL-15 pro-cytokine reactivates anti-tumor immunity with limited toxicity
| Autor: | Yueqi Cai, Yong Liang, Jiankun Zhu, Yang Xin Fu, Jingya Guo, Jiao Shen, Diyuan Xue, Hua Peng |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Interleukin-15
Tumor microenvironment medicine.drug_class medicine.medical_treatment Cell Biology CD8-Positive T-Lymphocytes Matrix metalloproteinase Biology Article Immune checkpoint Tyrosine-kinase inhibitor Mice Cytokine Cancer immunotherapy Interleukin 15 Neoplasms Tumor Microenvironment Cancer research medicine Animals Cytokines Immunotherapy Molecular Biology CD8 |
| Zdroj: | Cell Res |
| ISSN: | 1748-7838 1001-0602 |
| DOI: | 10.1038/s41422-021-00543-4 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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