Losartan controls immune checkpoint blocker-induced edema and improves survival in glioblastoma mouse models.
Losartan controls immune checkpoint blocker-induced edema and improves survival in glioblastoma mouse models.
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DOI：
10.1073/pnas.2219199120
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发表时间：
2023-02-07
影响因子：
11.1
通讯作者：
Jain, Rakesh K.
中科院分区：
文献类型：
--
作者：
Datta, Meenal;Chatterjee, Sampurna;Perez, Elizabeth M.;Gritsch, Simon;Roberge, Sylvie;Duquette, Mark;Chen, Ivy X.;Naxerova, Kamila;Kumar, Ashwin S.;Ghosh, Mitraji;Emblem, Kyrre E.;Ng, Mei R.;Ho, Willia W.;Kumar, Pragya;Krsihnan, Shanmugaraja;Dong, Xinyu;Speranza, Maria C.;Neagu, Martha R.;Iorgulescu, Bryan;Huang, Raymond Y.;Youssef, Gilbert;Reardon, David A.;Sharpe, Arlene H.;Freeman, Gordon J.;Suva, Mario L.;Xu, Lei;Jain, Rakesh K.
关键词：
改善大多数胶质母细胞瘤患者的免疫治疗结果仍然是一个严重未满足的需求。在胶质母细胞瘤小鼠模型中，使用安全、经济实惠且广泛处方的抗高血压药物（氯沙坦）克服了免疫相关不良事件，增强了抗肿瘤免疫活性，并改善了免疫检查点阻断剂治疗的生存结局。小鼠生物标志物模型提供了对治疗前肿瘤微环境中存在的免疫治疗反应的细胞介质的关键见解。本文所示的结果为将来在胶质母细胞瘤患者中测试氯沙坦与免疫检查点阻断的组合的临床研究奠定了基础。免疫检查点阻断剂（ICBs）在所有III期胶质母细胞瘤试验中均失败。在这里，我们发现ICBs在一些胶质母细胞瘤患者和小鼠中诱导脑水肿。通过单细胞RNA测序，活体成像和小鼠CD8+ T细胞阻断研究，我们证明了这种水肿是由抗程序性死亡1（PD1）抗体治疗后破坏血液肿瘤屏障的炎症反应引起的。血管紧张素受体阻滞剂氯沙坦代替免疫抑制性皮质类固醇，预防了这种ICB诱导的水肿，并重新编程了肿瘤微环境，治愈了20%的小鼠，与标准治疗相结合，治愈率提高到40%。使用双半球肿瘤模型，我们在氯沙坦+抗PD1治疗前确定了一个“热”肿瘤免疫特征，该特征可预测长期生存。我们的研究结果为在胶质母细胞瘤患者中测试氯沙坦与ICB的关系提供了依据和相关的生物标志物。
Improving immunotherapy outcomes for the majority of glioblastoma patients remains a critically unmet need. In mouse models of glioblastoma, the use of a safe, affordable, and widely prescribed antihypertensive agent (losartan) overcomes immune-related adverse events, enhances antitumor immune activity, and improves survival outcomes of immune checkpoint blocker therapy. A mouse biomarker model provides key insights into cellular mediators of immunotherapy response that are present in the tumor microenvironment prior to treatment. The results shown here serve as a foundation for future clinical studies testing the combination of losartan with immune checkpoint blockade in glioblastoma patients. Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma trials. Here, we found that ICBs induce cerebral edema in some patients and mice with glioblastoma. Through single-cell RNA sequencing, intravital imaging, and CD8+ T cell blocking studies in mice, we demonstrated that this edema results from an inflammatory response following antiprogrammed death 1 (PD1) antibody treatment that disrupts the blood–tumor barrier. Used in lieu of immunosuppressive corticosteroids, the angiotensin receptor blocker losartan prevented this ICB-induced edema and reprogrammed the tumor microenvironment, curing 20% of mice which increased to 40% in combination with standard of care treatment. Using a bihemispheric tumor model, we identified a “hot” tumor immune signature prior to losartan+anti-PD1 therapy that predicted long-term survival. Our findings provide the rationale and associated biomarkers to test losartan with ICBs in glioblastoma patients.
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影响因子：
28.2
作者：
Incio J;Liu H;Suboj P;Chin SM;Chen IX;Pinter M;Ng MR;Nia HT;Grahovac J;Kao S;Babykutty S;Huang Y;Jung K;Rahbari NN;Han X;Chauhan VP;Martin JD;Kahn J;Huang P;Desphande V;Michaelson J;Michelakos TP;Ferrone CR;Soares R;Boucher Y;Fukumura D;Jain RK
通讯作者：
Jain RK
影响因子：
8.4
作者：
Drobni, Zsofia D.;Michielin, Olivier;Quinaglia, Thiago;Zlotoff, Daniel A.;Zubiri, Leyre;Gilman, Hannah K.;Supraja, Sama;Merkely, Bela;Muller, Veronika;Sullivan, Ryan J.;Reynolds, Kerry L.;Pittet, Michael J.;Jain, Rakesh K.;Neilan, Tomas G.
通讯作者：
Neilan, Tomas G.
影响因子：
50.3
作者：
Jain RK
通讯作者：
Jain RK
影响因子：
3.2
作者：
Jain RK;Skelton Iv WP;Pond GR;Naqvi M;Kim Y;Curran C;Freeman D;Nuzzo PV;Alaiwi SA;Nassar AH;Jain RK;Sonpavde G
通讯作者：
Sonpavde G
DOI：
10.1073/pnas.1525360113
发表时间：
2016-04-19
影响因子：
11.1
作者：
Kloepper, Jonas;Riedemann, Lars;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.