Suppressive stroma-immune prognostic signature impedes immunotherapy in ovarian cancer and can be reversed by PDGFRB inhibitors.
Suppressive stroma-immune prognostic signature impedes immunotherapy in ovarian cancer and can be reversed by PDGFRB inhibitors.
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抑制性间质免疫预后特征阻碍卵巢癌的免疫治疗，并可被PDGFRB抑制剂逆转。
DOI：
10.1186/s12967-023-04422-x
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发表时间：
2023-09-01
影响因子：
7.4
通讯作者：
Zhu, Xiao-Feng
中科院分区：
文献类型：
--
作者：
Yang, Dong;Duan, Mei-Han;Yuan, Qiu-Er;Li, Zhi-Ling;Luo, Chuang-Hua;Cui, Lan-Yue;Li, Li-Chao;Xiao, Ying;Zhu, Xian-Ying;Zhang, Hai-Liang;Feng, Gong-Kan;Liu, Guo-Chen;Deng, Rong;Li, Jun-Dong;Zhu, Xiao-Feng
卵巢癌作为最致命的妇科癌症，具有免疫应答的潜力。然而，通过免疫疗法如免疫检查点阻断仅实现了适度的治疗效果。本研究的目的是提出一种广义的基质免疫预后标志（SIPS），以确定谁可能受益于免疫治疗的OV患者。研究中纳入的2097例OV患者均为III/IV期高级别浆液性卵巢癌。收集了470个免疫相关的签名，并通过考克斯回归和Lasso算法进行分析，以概括出可信的SIPS。进一步分析了SIPS信号与肿瘤微环境之间的相关性。通过靶向主要抑制性基质组分（CAF，癌症相关成纤维细胞）在体外和体内进一步验证了由SIPS指示的基质的关键免疫抑制作用。通过四种机器学习方法预测肿瘤免疫亚型，基质免疫特征被升级为23个基因的特征。SIPS有效地区分了训练和验证队列中的高风险个体，其中高SIPS成功地预测了几个免疫治疗队列中更差的生存率。SIPS信号与基质成分，特别是肿瘤微环境中的CAF和免疫抑制细胞正相关，表明关键的抑制性基质免疫网络。CAF的标志物PDGFRB抑制剂和一线PARP抑制剂的组合基本上抑制了肿瘤生长并促进了携带OV的小鼠的存活。将基质免疫标签升级为23基因标签以提高临床实用性。几种抑制间质免疫特征的药物类型，如EGFR抑制剂，可能是卵巢癌潜在免疫抑制剂组合的候选药物。间质免疫特征可以有效预测OV患者的免疫敏感性。针对卵巢癌间质的免疫治疗和辅助药物可提高卵巢癌的免疫治疗效果。在线版本包含补充材料，可通过10.1186/s12967-023-04422-x获得。
As the most lethal gynecologic cancer, ovarian cancer (OV) holds the potential of being immunotherapy-responsive. However, only modest therapeutic effects have been achieved by immunotherapies such as immune checkpoint blockade. This study aims to propose a generalized stroma-immune prognostic signature (SIPS) to identify OV patients who may benefit from immunotherapy. The 2097 OV patients included in the study were significant with high-grade serous ovarian cancer in the III/IV stage. The 470 immune-related signatures were collected and analyzed by the Cox regression and Lasso algorithm to generalize a credible SIPS. Correlations between the SIPS signature and tumor microenvironment were further analyzed. The critical immunosuppressive role of stroma indicated by the SIPS was further validated by targeting the major suppressive stroma component (CAFs, Cancer-associated fibroblasts) in vitro and in vivo. With four machine-learning methods predicting tumor immune subtypes, the stroma-immune signature was upgraded to a 23-gene signature. The SIPS effectively discriminated the high-risk individuals in the training and validating cohorts, where the high SIPS succeeded in predicting worse survival in several immunotherapy cohorts. The SIPS signature was positively correlated with stroma components, especially CAFs and immunosuppressive cells in the tumor microenvironment, indicating the critical suppressive stroma-immune network. The combination of CAFs’ marker PDGFRB inhibitors and frontline PARP inhibitors substantially inhibited tumor growth and promoted the survival of OV-bearing mice. The stroma-immune signature was upgraded to a 23-gene signature to improve clinical utility. Several drug types that suppress stroma-immune signatures, such as EGFR inhibitors, could be candidates for potential immunotherapeutic combinations in ovarian cancer. The stroma-immune signature could efficiently predict the immunotherapeutic sensitivity of OV patients. Immunotherapy and auxiliary drugs targeting stroma could enhance immunotherapeutic efficacy in ovarian cancer. The online version contains supplementary material available at 10.1186/s12967-023-04422-x.
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影响因子：
64.5
作者：
Zhang H;Liu T;Zhang Z;Payne SH;Zhang B;McDermott JE;Zhou JY;Petyuk VA;Chen L;Ray D;Sun S;Yang F;Chen L;Wang J;Shah P;Cha SW;Aiyetan P;Woo S;Tian Y;Gritsenko MA;Clauss TR;Choi C;Monroe ME;Thomas S;Nie S;Wu C;Moore RJ;Yu KH;Tabb DL;Fenyö D;Bafna V;Wang Y;Rodriguez H;Boja ES;Hiltke T;Rivers RC;Sokoll L;Zhu H;Shih IM;Cope L;Pandey A;Zhang B;Snyder MP;Levine DA;Smith RD;Chan DW;Rodland KD;CPTAC Investigators
通讯作者：
CPTAC Investigators
与肿瘤微环境相关的九个基因特征可预测卵巢癌的总体生存率
影响因子：
5.2
作者：
Ding, Qi;Dong, Shanshan;Zeng, Yong
通讯作者：
Zeng, Yong
影响因子：
11
作者：
Tiwari, Aadhya;Trivedi, Rakesh;Lin, Shiaw-Yih
通讯作者：
Lin, Shiaw-Yih
影响因子：
16.6
作者：
Nguyen L;W M Martens J;Van Hoeck A;Cuppen E
通讯作者：
Cuppen E
DOI：
10.1056/nejmoa1200694
发表时间：
2012-06-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Brahmer JR;Tykodi SS;Chow LQ;Hwu WJ;Topalian SL;Hwu P;Drake CG;Camacho LH;Kauh J;Odunsi K;Pitot HC;Hamid O;Bhatia S;Martins R;Eaton K;Chen S;Salay TM;Alaparthy S;Grosso JF;Korman AJ;Parker SM;Agrawal S;Goldberg SM;Pardoll DM;Gupta A;Wigginton JM
通讯作者：
Wigginton JM