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SCI 7 August 2019 Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold
New opportunities are needed to increase immune checkpoint blockade (ICB) benefit. Whereas the interferon (IFN)g pathway harbors both ICB resistance factors and therapeutic opportunities, this has not been systematically investigated for IFNg-independent signaling routes. A genome-wide CRISPR/Cas9 screen to sensitize IFNg receptor-deficient tumor cells to CD8 T cell elimination uncovered several hits mapping to the tumor necrosis factor (TNF) pathway. Clinically, we show that TNF antitumor activity is only limited in tumors at baseline and in ICB non-responders, correlating with its low abundance. Taking advantage of the genetic screen, we demonstrate that ablation of the top hit, TRAF2, lowers the TNF cytotoxicity threshold in tumors by redirecting TNF signaling to favor RIPK1-dependent apoptosis. TRAF2 loss greatly enhanced the therapeutic potential of pharmacologic inhibition of its interaction partner cIAP, another screen hit, thereby cooperating with ICB. Our results suggest that selective reduction of the TNF cytotoxicity threshold increases the susceptibility of tumors to immunotherapy. 需要新的机会来增加免疫检查点封锁（ICB）的益处。尽管干扰素（IFN）g途径具有ICB抗性因子和治疗机会，但尚未系统地研究IFNg非依赖性信号传导途径。全基因组CRISPR / Cas9筛选使IFNg受体缺陷的肿瘤细胞对CD8T细胞消除敏感，揭示了几种映射到肿瘤坏死因子（TNF）途径的命中。临床上，我们显示TNF抗肿瘤活性仅限于基线和ICB无应答者的肿瘤，与其低丰度相关。利用遗传筛选，我们证明顶部命中TRAF2的消融通过重定向TNF信号传导有利于RIPK1依赖性细胞凋亡而降低肿瘤中的TNF细胞毒性阈值。TRAF2的损失大大增强了其相互作用伴侣cIAP的药理学抑制的治疗潜力，这是另一个筛选，从而与ICB合作。我们的结果表明选择性降低TNF细胞毒性阈值增加了肿瘤对免疫疗法的易感性。 喜欢SCI天天读的理由 陪您一起学习SCI医学论文 每天5分钟，让自己的英语牛逼起来 特殊福利让您惊喜连连 |
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