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SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion
Cell ( IF 45.5 ) Pub Date : 2024-01-31 , DOI: 10.1016/j.cell.2024.01.008
Giuseppe Leuzzi 1 , Alessandro Vasciaveo 2 , Angelo Taglialatela 1 , Xiao Chen 1 , Tessa M Firestone 3 , Allison R Hickman 3 , Wendy Mao 4 , Tanay Thakar 1 , Alina Vaitsiankova 1 , Jen-Wei Huang 1 , Raquel Cuella-Martin 1 , Samuel B Hayward 1 , Jordan S Kesner 2 , Ali Ghasemzadeh 4 , Tarun S Nambiar 1 , Patricia Ho 5 , Alexander Rialdi 6 , Maxime Hebrard 7 , Yinglu Li 1 , Jinmei Gao 8 , Saarang Gopinath 3 , Oluwatobi A Adeleke 3 , Bryan J Venters 3 , Charles G Drake 9 , Richard Baer 10 , Benjamin Izar 11 , Ernesto Guccione 6 , Michael-Christopher Keogh 3 , Raphael Guerois 8 , Lu Sun 3 , Chao Lu 1 , Andrea Califano 12 , Alberto Ciccia 13
Cell ( IF 45.5 ) Pub Date : 2024-01-31 , DOI: 10.1016/j.cell.2024.01.008
Giuseppe Leuzzi 1 , Alessandro Vasciaveo 2 , Angelo Taglialatela 1 , Xiao Chen 1 , Tessa M Firestone 3 , Allison R Hickman 3 , Wendy Mao 4 , Tanay Thakar 1 , Alina Vaitsiankova 1 , Jen-Wei Huang 1 , Raquel Cuella-Martin 1 , Samuel B Hayward 1 , Jordan S Kesner 2 , Ali Ghasemzadeh 4 , Tarun S Nambiar 1 , Patricia Ho 5 , Alexander Rialdi 6 , Maxime Hebrard 7 , Yinglu Li 1 , Jinmei Gao 8 , Saarang Gopinath 3 , Oluwatobi A Adeleke 3 , Bryan J Venters 3 , Charles G Drake 9 , Richard Baer 10 , Benjamin Izar 11 , Ernesto Guccione 6 , Michael-Christopher Keogh 3 , Raphael Guerois 8 , Lu Sun 3 , Chao Lu 1 , Andrea Califano 12 , Alberto Ciccia 13
Affiliation
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Genomic instability can trigger cancer-intrinsic innate immune responses that promote tumor rejection. However, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. Here, we identify the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 limits endogenous DNA damage, thereby suppressing cGAS-STING-dependent signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a PD-L1 transcriptional regulatory element, thereby promoting PD-L1 expression in cancer cells. SMARCAL1 loss hinders the ability of tumor cells to induce PD-L1 in response to genomic instability, enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these studies uncover SMARCAL1 as a promising target for cancer immunotherapy.
中文翻译：
SMARCAL1 是先天免疫信号转导和 PD-L1 表达的双重调节因子，可促进肿瘤免疫逃逸
基因组不稳定性可触发癌症内在先天免疫反应，从而促进肿瘤排斥反应。然而，癌细胞通常通过过表达免疫检查点调节因子（如 PD-L1）来逃避这些反应。在这里，我们将 SNF2 家族 DNA 转位酶 SMARCAL1 确定为通过双重机制促进肿瘤免疫逃避的因素，该机制涉及抑制先天免疫信号传导和诱导 PD-L1 介导的免疫检查点反应。从机制上讲，SMARCAL1 限制了内源性 DNA 损伤，从而抑制了癌细胞生长过程中的 cGAS-STING 依赖性信号传导。同时，它与 AP-1 家族成员 JUN 合作，维持 PD-L1 转录调节元件的染色质可及性，从而促进癌细胞中 PD-L1 的表达。在小鼠黑色素瘤模型中，SMARCAL1 缺失阻碍了肿瘤细胞响应基因组不稳定性诱导 PD-L1 的能力，增强了抗肿瘤免疫反应并使肿瘤对免疫检查点阻断敏感。总的来说，这些研究揭示了 SMARCAL1 是癌症免疫治疗的有前途的靶点。
更新日期：2024-01-31
中文翻译：
SMARCAL1 是先天免疫信号转导和 PD-L1 表达的双重调节因子，可促进肿瘤免疫逃逸
基因组不稳定性可触发癌症内在先天免疫反应，从而促进肿瘤排斥反应。然而，癌细胞通常通过过表达免疫检查点调节因子（如 PD-L1）来逃避这些反应。在这里，我们将 SNF2 家族 DNA 转位酶 SMARCAL1 确定为通过双重机制促进肿瘤免疫逃避的因素，该机制涉及抑制先天免疫信号传导和诱导 PD-L1 介导的免疫检查点反应。从机制上讲，SMARCAL1 限制了内源性 DNA 损伤，从而抑制了癌细胞生长过程中的 cGAS-STING 依赖性信号传导。同时，它与 AP-1 家族成员 JUN 合作，维持 PD-L1 转录调节元件的染色质可及性，从而促进癌细胞中 PD-L1 的表达。在小鼠黑色素瘤模型中，SMARCAL1 缺失阻碍了肿瘤细胞响应基因组不稳定性诱导 PD-L1 的能力，增强了抗肿瘤免疫反应并使肿瘤对免疫检查点阻断敏感。总的来说，这些研究揭示了 SMARCAL1 是癌症免疫治疗的有前途的靶点。
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