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Tumor-conditional IL-15 pro-cytokine reactivates anti-tumor immunity with limited toxicity
肿瘤条件性 IL-15 前细胞因子以有限的毒性重新激活抗肿瘤免疫
腫瘍条件付きIL-15プロサイトカインは、限られた毒性で抗腫瘍免疫を再活性化します
종양 조건부 IL-15 프로 사이토카인은 제한된 독성으로 항종양 면역을 재활성화합니다.
La pro-citocina de IL-15 condicional al tumor reactiva la inmunidad antitumoral con toxicidad limitada
La pro-cytokine IL-15 conditionnelle aux tumeurs réactive l'immunité anti-tumorale avec une toxicité limitée
Обусловленный опухолью про-цитокин IL-15 реактивирует противоопухолевый иммунитет с ограниченной токсичностью
Jingya Guo 郭静雅 ¹ ², Yong Liang 梁永 ³, Diyuan Xue 薛娣媛 ¹ ², Jiao Shen ¹ ², Yueqi Cai ¹ ², Jiankun Zhu ³, Yang-Xin Fu 傅阳心 ³, Hua Peng 彭华 ¹
¹ Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China 中国科学院 生物物理研究所 感染与免疫重点实验室
² University of Chinese Academy of Sciences, Beijing, China 中国科学院大学
³ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
Cell Research, 10 August 2021
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.
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