澳大利莫纳什大学Nicholas D. Huntington团队的一项最新研究研制了靶向IL-15R信号增强自然杀伤细胞抗肿瘤免疫。相关论文于2025年6月12日发表于国际顶尖学术期刊《癌细胞》杂志上。

该课题组进行了全基因组CRISPR筛选，揭示了自然杀伤细胞（NK）中IL-15R的完整信号传导机制，发现泛素依赖性IL-15R降解是抑制IL-15R信号传导的主要机制。关键靶点包括NEDD8 E2偶联酶UBE2F、泛素E3连接酶ARIH2和Cullin-5 RING E3连接酶（CRL5）成员。研究组发现UBE2F是类化修饰和CUL5激活所必需的，而ARIH2则有助于crl5介导的IL-15RB降解。消融ARIH2或UBE2F可增加IL-15RB表面表达并增强信号传导，导致促炎细胞因子产生和增强自然和CAR介导的细胞毒性。在缺乏Arih2， Rnf7或Ube2f的小鼠中，课题组研究人员观察到IL-15R高反应NK细胞对原发性和弥散性转移性肿瘤表现出优越的体内抗肿瘤免疫。因此，该课题组人员已经确定了UBE2F和ARIH2酶作为可处理的免疫治疗药物靶点。

据介绍，白细胞介素-15受体（IL-15R）激动剂在临床前模型中诱导抗肿瘤免疫。然而，剂量限制性毒性阻碍了它们的临床发展。

附：英文原文

Title: Enhancing anti-tumor immunity of natural killer cells through targeting IL-15R signaling

Author: Iva Nikolic, Joseph Cursons, Benjamin Shields, Stephane Chappaz, Harrison Sudholz, Xiangpeng Meng, Patrick Constantinescu, Reshma Vijayakumaran, Michael D’Angelo, Momeneh Foroutan, David Ladd, Matthew Veldman, Jason Glab, Tahlia Procter, Hae-Young Park, Julian Contet, Felix Deuss, Kahlia Wong, Yi Sun, Richard Berry, Jai Rautela, Nicholas D. Huntington

Issue&Volume: 2025-06-12

Abstract: Interleukin-15 receptor (IL-15R) agonists induce anti-tumor immunity in pre-clinical models. However, dose-limiting toxicity has hampered their clinical development. We performed genome-wide CRISPR screens to reveal the complete IL-15R signaling mechanism in natural killer (NK) cells and discovered that ubiquitin-dependent IL-15R degradation is the dominant mechanism restraining IL-15R signaling. Key hits included the NEDD8 E2-conjugating enzyme UBE2F, the ubiquitin E3-ligase ARIH2, and Cullin-5 RING E3 ligase (CRL5) members. We found that UBE2F was required for neddylation and activation of CUL5, whereas ARIH2 contributed to CRL5-mediated IL-15RB degradation. Ablation of ARIH2 or UBE2F increased IL-15RB surface expression and enhanced signaling, resulting in proinflammatory cytokine production and augmented natural and CAR-mediated cytotoxicity. In mice lacking Arih2, Rnf7, or Ube2f, we observed that the IL-15R hyperresponsive NK cells exhibited superior in vivo anti-tumor immunity against primary and disseminated metastatic tumors. Thus, we have identified the enzymes UBE2F and ARIH2 as tractable immunotherapy drug targets.

DOI: 10.1016/j.ccell.2025.05.011

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00220-X