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Targeting the chromatin effector Pygo2 promotes cytotoxic T cell responses and overcomes immunotherapy resistance in prostate cancer
Science Immunology ( IF 17.6 ) Pub Date : 2023-03-10 , DOI: 10.1126/sciimmunol.ade4656
Yini Zhu 1, 2 , Yun Zhao 1 , Jiling Wen 1 , Sheng Liu 3 , Tianhe Huang 1 , Ishita Hatial 4 , Xiaoxia Peng 1 , Hawraa Al Janabi 1 , Gang Huang 1 , Jackson Mittlesteadt 1 , Michael Cheng 5 , Atul Bhardwaj 4 , Brandon L Ashfeld 4 , Kenneth R Kao 6 , Dean Y Maeda 7 , Xing Dai 8 , Olaf Wiest 4 , Brian S J Blagg 4 , Xuemin Lu 1 , Liang Cheng 9, 10 , Jun Wan 3, 11, 12 , Xin Lu 1, 2, 13
Affiliation  

The noninflamed microenvironment in prostate cancer represents a barrier to immunotherapy. Genetic alterations underlying cancer cell–intrinsic oncogenic signaling are increasingly appreciated for their role in shaping the immune landscape. Recently, we identified Pygopus 2 ( PYGO2 ) as the driver oncogene for the amplicon at 1q21.3 in prostate cancer. Here, using transgenic mouse models of metastatic prostate adenocarcinoma, we found that Pygo2 deletion decelerated tumor progression, diminished metastases, and extended survival. Pygo2 loss augmented the activation and infiltration of cytotoxic T lymphocytes (CTLs) and sensitized tumor cells to T cell killing. Mechanistically, Pygo2 orchestrated a p53/Sp1/Kit/Ido1 signaling network to foster a microenvironment hostile to CTLs. Genetic or pharmacological inhibition of Pygo2 enhanced the antitumor efficacy of immunotherapies using immune checkpoint blockade (ICB), adoptive cell transfer, or agents inhibiting myeloid-derived suppressor cells. In human prostate cancer samples, Pygo2 expression was inversely correlated with the infiltration of CD8 + T cells. Analysis of the ICB clinical data showed association between high PYGO2 level and worse outcome. Together, our results highlight a potential path to improve immunotherapy using Pygo2-targeted therapy for advanced prostate cancer.

中文翻译:


靶向染色质效应器 Pygo2 促进细胞毒性 T 细胞反应并克服前列腺癌的免疫治疗耐药性



前列腺癌中的非炎症微环境是免疫治疗的障碍。癌细胞内在致癌信号传导背后的遗传改变因其在塑造免疫景观中的作用而日益受到重视。最近,我们发现了 Pygopu​​s 2( PYGO2 ) 作为前列腺癌中 1q21.3 扩增子的驱动癌基因。在这里,使用转移性前列腺腺癌的转基因小鼠模型,我们发现pygo2缺失可以减缓肿瘤进展、减少转移并延长生存期。 Pygo2 的缺失增强了细胞毒性 T 淋巴细胞 (CTL) 的激活和浸润,并使肿瘤细胞对 T 细胞杀伤变得敏感。从机制上讲,Pygo2 精心策划了 p53/Sp1/Kit/Ido1 信号网络,以培育对 CTL 不利的微环境。 Pygo2 的遗传或药理学抑制增强了使用免疫检查点阻断 (ICB)、过继细胞转移或抑制骨髓源性抑制细胞的药物的免疫疗法的抗肿瘤功效。在人类前列腺癌样本中,Pygo2 表达与 CD8 浸润呈负相关+ T 细胞。 ICB 临床数据分析表明,高PYGO2水平和更差的结果。总之,我们的结果凸显了使用 Pygo2 靶向疗法改善晚期前列腺癌免疫疗法的潜在途径。
更新日期:2023-03-10
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