Immune landscape of a genetically engineered murine model of glioma compared with human glioma.
Immune landscape of a genetically engineered murine model of glioma compared with human glioma.
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DOI：
10.1172/jci.insight.148990
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发表时间：
2022-06-22
期刊：
影响因子：
8
通讯作者：
Hu, Jian
中科院分区：
文献类型：
--
作者：
Zamler, Daniel B.;Shingu, Takashi;Kahn, Laura M.;Huntoon, Kristin;Kassab, Cynthia;Ott, Martina;Tomczak, Katarzyna;Liu, Jintan;Li, Yating;Lai, Ivy;Zorilla-Veloz, Rocio;Yee, Cassian;Rai, Kunal;Kim, Betty Y. S.;Watowich, Stephanie S.;Heimberger, Amy B.;Draetta, Giulio F.;Hu, Jian
靶向胶质母细胞瘤（GBM）的新治疗策略在临床上经常失败，部分原因是正在测试假设的临床前模型不能概括人类疾病。为了解决这一挑战，我们利用我们先前开发的人GBM的自发Qk/Trp 53/Pten（QPP）三重敲除模型，比较QPP小鼠的免疫微环境与患者来源的肿瘤的免疫微环境，以确定该模型是否提供了深入了解肿瘤生理病理学和治疗剂的临床前评价的机会。对来自QPP小鼠和患有神经胶质瘤的患者的植入和自发肿瘤的免疫谱分析和单细胞测序揭示了主要是骨髓细胞的肿瘤内免疫组分（例如，单核细胞、巨噬细胞和小神经胶质细胞），具有少量的T、B和NK细胞。当比较自发和植入小鼠样品时，我们在植入模型中发现更多的中性粒细胞以及T和NK细胞。与来自低级别胶质瘤的样本相比，来自人类高级别胶质瘤的样本中的中性粒细胞和T细胞及NK细胞丰度增加。总体而言，我们的数据表明，我们的植入和自发QPP模型概括了人类胶质瘤肿瘤微环境的免疫抑制性髓样细胞占主导地位的性质。我们的模型提供了一个合适的工具，调查复杂的免疫区室的胶质瘤。
Novel therapeutic strategies targeting glioblastoma (GBM) often fail in the clinic, partly because preclinical models in which hypotheses are being tested do not recapitulate human disease. To address this challenge, we took advantage of our previously developed spontaneous Qk/Trp53/Pten (QPP) triple-knockout model of human GBM, comparing the immune microenvironment of QPP mice with that of patient-derived tumors to determine whether this model provides opportunity for gaining insights into tumor physiopathology and preclinical evaluation of therapeutic agents. Immune profiling analyses and single-cell sequencing of implanted and spontaneous tumors from QPP mice and from patients with glioma revealed intratumoral immune components that were predominantly myeloid cells (e.g., monocytes, macrophages, and microglia), with minor populations of T, B, and NK cells. When comparing spontaneous and implanted mouse samples, we found more neutrophils and T and NK cells in the implanted model. Neutrophils and T and NK cells were increased in abundance in samples derived from human high-grade glioma compared with those derived from low-grade glioma. Overall, our data demonstrate that our implanted and spontaneous QPP models recapitulate the immunosuppressive myeloid-dominant nature of the tumor microenvironment of human gliomas. Our model provides a suitable tool for investigating the complex immune compartment of gliomas.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
7.3
作者：
Chen Z;Hambardzumyan D
通讯作者：
Hambardzumyan D
影响因子：
4.1
作者：
AKBASAK, A;OLDFIELD, EH;SARIS, SC
通讯作者：
SARIS, SC
影响因子：
15.9
作者：
Hussain, S. Farzana;Yang, David;Heimberger, Amy B.
通讯作者：
Heimberger, Amy B.
DOI：
10.1073/pnas.1222738110
发表时间：
2013-02-19
影响因子：
11.1
作者：
Shay, Tal;Jojic, Vladimir;Regev, Aviv
通讯作者：
Regev, Aviv