PDF(Pubmed)
Abstract：
Immune checkpoint blockade therapy aims to activate the immune system to eliminate cancer cells. However, clinical benefits are only recorded in a subset of patients. Here, we leverage genome-wide CRISPR/Cas9 screens in a Tumor-Immune co-Culture System focusing on triple-negative breast cancer (TNBC). We reveal that NEDD8 loss in cancer cells causes a vulnerability to nivolumab (anti-PD-1). Genetic deletion of NEDD8 only delays cell division initially but cell proliferation is unaffected after recovery. Since the NEDD8 gene is commonly essential, we validate this observation with additional CRISPR screens and uncover enhanced immunogenicity in NEDD8 deficient cells using proteomics. In female immunocompetent mice, PD-1 blockade lacks efficacy against established EO771 breast cancer tumors. In contrast, we observe tumor regression mediated by CD8+ T cells against Nedd8 deficient EO771 tumors after PD-1 blockade. In essence, we provide evidence that NEDD8 is conditionally essential in TNBC and presents as a synergistic drug target for PD-1/L1 blockade therapy.
摘要：
免疫检查点阻断疗法旨在激活免疫系统以消除癌细胞。然而,临床获益仅记录在一部分患者中.这里,我们在肿瘤免疫共培养系统中利用全基因组CRISPR/Cas9筛选，重点关注三阴性乳腺癌（TNBC）。我们发现NEDD8在癌细胞中的丢失导致nivolumab（抗PD-1）的脆弱性。NEDD8的遗传缺失最初仅延迟细胞分裂，但恢复后细胞增殖不受影响。由于NEDD8基因通常是必需的，我们通过额外的CRISPR筛选验证了这一观察结果,并使用蛋白质组学揭示了NEDD8缺陷细胞中增强的免疫原性.在雌性免疫活性小鼠中，PD-1阻断缺乏对已建立的EO771乳腺癌肿瘤的功效。相比之下,我们观察到PD-1阻断后CD8+T细胞介导的针对Nedd8缺陷型EO771肿瘤的肿瘤消退。实质上,我们提供的证据表明NEDD8在TNBC中是有条件必需的,并且是PD-1/L1阻断治疗的协同药物靶点.
