Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer.
Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer.
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DOI：
10.1038/s41467-023-37568-9
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发表时间：
2023-04-27
影响因子：
16.6
通讯作者：
Meeks, Joshua J.
中科院分区：
文献类型：
--
作者：
Robertson, A. Gordon;Meghani, Khyati;Cooley, Lauren Folgosa;McLaughlin, Kimberly A.;Fall, Leigh Ann;Yu, Yanni;Castro, Mauro A. A.;Groeneveld, Clarice S.;de Reynies, Aurelien;Nazarov, Vadim I.;Tsvetkov, Vasily O.;Choy, Bonnie;Raggi, Daniele;Marandino, Laura;Montorsi, Francesco;Powles, Thomas;Necchi, Andrea;Meeks, Joshua J.
检查点免疫疗法（CPI）提高了一些晚期膀胱癌（BCa）患者的生存率。然而，大多数患者没有反应。在这里，我们使用结合转录和遗传谱与数字空间谱的整合方法，对PURE01新辅助派姆单抗免疫治疗试验中治疗前后肿瘤的肿瘤和免疫微环境进行了表征。我们确定了五种不同的遗传和转录组程序，并在一项独立的新辅助CPI试验中验证了这些程序，以确定对CPI的反应或抗性特征。通过对调控网络进行建模，我们在一种耐药亚型（S1， luminal排除）中鉴定出组蛋白去甲基化酶KDM5B是肿瘤免疫信号通路的抑制因子，并证明抑制KDM5B可增强fgfr3突变的BCa细胞的免疫原性。我们的研究确定了与CPI反应相关的特征，可用于对患者进行分子分层，并为对新辅助免疫治疗反应不佳的亚型提供治疗方案。膀胱癌患者对检查点免疫治疗的反应是高度可变的。在这里，作者使用RNA-seq， ATAC-seq和数字空间谱分析来自PURE01试验的治疗前和治疗后样本，以确定与治疗反应相关的亚型。
Checkpoint immunotherapy (CPI) has increased survival for some patients with advanced-stage bladder cancer (BCa). However, most patients do not respond. Here, we characterized the tumor and immune microenvironment in pre- and post-treatment tumors from the PURE01 neoadjuvant pembrolizumab immunotherapy trial, using a consolidative approach that combined transcriptional and genetic profiling with digital spatial profiling. We identify five distinctive genetic and transcriptomic programs and validate these in an independent neoadjuvant CPI trial to identify the features of response or resistance to CPI. By modeling the regulatory network, we identify the histone demethylase KDM5B as a repressor of tumor immune signaling pathways in one resistant subtype (S1, Luminal-excluded) and demonstrate that inhibition of KDM5B enhances immunogenicity in FGFR3-mutated BCa cells. Our study identifies signatures associated with response to CPI that can be used to molecularly stratify patients and suggests therapeutic alternatives for subtypes with poor response to neoadjuvant immunotherapy. The response to checkpoint immunotherapy within bladder cancer patients is highly variable. Here, the authors use RNA-seq, ATAC-seq and digital spatial profiling of pre- and post-treatment samples from the PURE01 trial to identify subtypes associated with treatment response.
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影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
单细胞 RNA 测序强调了炎性癌症相关成纤维细胞在膀胱尿路上皮癌中的作用。
影响因子：
16.6
作者：
Chen Z;Zhou L;Liu L;Hou Y;Xiong M;Yang Y;Hu J;Chen K
通讯作者：
Chen K
影响因子：
37.3
作者：
Hayami S;Yoshimatsu M;Veerakumarasivam A;Unoki M;Iwai Y;Tsunoda T;Field HI;Kelly JD;Neal DE;Yamaue H;Ponder BA;Nakamura Y;Hamamoto R
通讯作者：
Hamamoto R
影响因子：
14.9
作者：
Gillespie M;Jassal B;Stephan R;Milacic M;Rothfels K;Senff-Ribeiro A;Griss J;Sevilla C;Matthews L;Gong C;Deng C;Varusai T;Ragueneau E;Haider Y;May B;Shamovsky V;Weiser J;Brunson T;Sanati N;Beckman L;Shao X;Fabregat A;Sidiropoulos K;Murillo J;Viteri G;Cook J;Shorser S;Bader G;Demir E;Sander C;Haw R;Wu G;Stein L;Hermjakob H;D'Eustachio P
通讯作者：
D'Eustachio P
影响因子：
4.6
作者：
Guo, Charles C.;Bondaruk, Jolanta;Czerniak, Bogdan
通讯作者：
Czerniak, Bogdan