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Tumor Cell-Intrinsic USP22 Suppresses Antitumor Immunity in Pancreatic Cancer.
Cancer Immunology Research ( IF 8.1 ) Pub Date : 2019-12-23 , DOI: 10.1158/2326-6066.cir-19-0661
Jinyang Li 1, 2, 3, 4 , Salina Yuan 1, 2, 3, 4 , Robert J Norgard 1, 2, 3, 4 , Fangxue Yan 4, 5 , Taiji Yamazoe 1, 2, 3 , Andrés Blanco 4, 5 , Ben Z Stanger 1, 2, 3, 6
Affiliation  

Although immune checkpoint blockade (ICB) improves clinical outcome in several types of malignancies, pancreatic ductal adenocarcinoma (PDA) remains refractory to this therapy. Preclinical studies have demonstrated that the relative abundance of suppressive myeloid cells versus cytotoxic T cells determines the efficacy of combination immunotherapies, which include ICB. Here, we evaluated the role of the ubiquitin-specific protease 22 (USP22) as a regulator of the immune tumor microenvironment (TME) in PDA. We report that deletion of USP22 in pancreatic tumor cells reduced the infiltration of myeloid cells and promoted the infiltration of T cells and natural killer (NK) cells, leading to an improved response to combination immunotherapy. We also showed that ablation of tumor cell-intrinsic USP22 suppressed metastasis of pancreatic tumor cells in a T-cell-dependent manner. Finally, we provide evidence that USP22 exerted its effects on the immune TME by reshaping the cancer cell transcriptome through its association with the deubiquitylase module of the SAGA/STAGA transcriptional coactivator complex. These results indicated that USP22 regulates immune infiltration and immunotherapy sensitivity in preclinical models of pancreatic cancer.

中文翻译:

肿瘤细胞固有的 USP22 抑制胰腺癌的抗肿瘤免疫。

尽管免疫检查点阻断 (ICB) 改善了几种恶性肿瘤的临床结果,但胰腺导管腺癌 (PDA) 仍然对这种治疗无效。临床前研究表明,抑制性骨髓细胞与细胞毒性 T 细胞的相对丰度决定了包括 ICB 在内的联合免疫疗法的功效。在这里,我们评估了泛素特异性蛋白酶 22 (USP22) 作为 PDA 中免疫肿瘤微环境 (TME) 调节剂的作用。我们报告说,胰腺肿瘤细胞中 USP22 的缺失减少了骨髓细胞的浸润并促进了 T 细胞和自然杀伤 (NK) 细胞的浸润,从而提高了对联合免疫疗法的反应。我们还表明,肿瘤细胞内在 USP22 的消融以 T 细胞依赖性方式抑制了胰腺肿瘤细胞的转移。最后,我们提供证据表明 USP22 通过与 SAGA/STAGA 转录共激活因子复合物的去泛素化酶模块的关联重塑癌细胞转录组,从而对免疫 TME 产生影响。这些结果表明,USP22 调节胰腺癌临床前模型中的免疫浸润和免疫治疗敏感性。
更新日期:2020-04-21
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