Division of Molecular Oncology and Immunology, Oncode Institute, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands.
Biomolecular Mass Spectrometry and Proteomics, Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH, Utrecht, the Netherlands.
Cell. 2019 Jul 25;178(3):585-599.e15. doi: 10.1016/j.cell.2019.06.014. Epub 2019 Jul 11.
New opportunities are needed to increase immune checkpoint blockade (ICB) benefit. Whereas the interferon (IFN)γ pathway harbors both ICB resistance factors and therapeutic opportunities, this has not been systematically investigated for IFNγ-independent signaling routes. A genome-wide CRISPR/Cas9 screen to sensitize IFNγ 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阻断（ICB）的获益。干扰素（IFN）γ途径既包含 ICB 抵抗因素，也包含治疗机会，但 IFNγ 非依赖性信号通路尚未得到系统研究。一项全基因组 CRISPR/Cas9 筛选旨在使 IFNγ 受体缺陷的肿瘤细胞对 CD8 T 细胞消除敏感，发现了几个与肿瘤坏死因子（TNF）途径相关的靶点。临床上，我们发现 TNF 的抗肿瘤活性仅在基线时和 ICB 无应答者的肿瘤中受到限制，这与其低丰度相关。利用遗传筛选，我们证明通过将 TNF 信号重新导向有利于 RIPK1 依赖性凋亡的方式，TRAF2 的缺失降低了肿瘤中 TNF 的细胞毒性阈值。TRAF2 的缺失极大地增强了其相互作用伙伴 cIAP 的药理学抑制的治疗潜力，这也是筛选的另一个靶点，从而与 ICB 协同作用。我们的结果表明，选择性降低 TNF 的细胞毒性阈值可增加肿瘤对免疫治疗的敏感性。
