PI3K{gamma} inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response [Medical Sciences],Proceedings of the National Academy of Sciences of the United States of America

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PI3K{gamma} inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response [Medical Sciences]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2021-04-20 , DOI: 10.1073/pnas.2009290118
Jie Li ₁ , Megan M Kaneda ₂ , Jun Ma ₁ , Ming Li ₁ , Ryan M Shepard ₂ , Kunal Patel ₃ , Tomoyuki Koga ₁ , Aaron Sarver ₄ , Frank Furnari ₅ , Beibei Xu ₁ , Sanjay Dhawan ₁ , Jianfang Ning ₁ , Hua Zhu _{1,

6} , Anhua Wu ₇ , Gan You _{1,

8} , Tao Jiang _{8,

9} , Andrew S Venteicher ₁ , Jeremy N Rich ₁₀ , Christopher K Glass ₁₁ , Judith A Varner ₁₂ , Clark C Chen ₁₃

Affiliation

Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455.
Moores Cancer Center, University of California San Diego, La Jolla, CA 92037.
Department of Neurosurgery, University of California, Los Angeles, CA 90095.
Institute for Health Informatics, University of Minnesota, Minneapolis, MN 55455.
Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA.
Department of Pediatrics, The First Hospital of China Medical University, Shenyang 110122, China.
Department of Neurosurgery, The First Hospital of China Medical University, Shenyang 110122, China.
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.
Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China.
Department of Medicine, Division of Regenerative Medicine, University of California San Diego, La Jolla, CA 92093.
Department of Medicine, University of California San Diego, La Jolla, CA 92093.
Department of Pathology, University of California San Diego, La Jolla, CA 92161.
Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455;

Precision medicine in oncology leverages clinical observations of exceptional response. Toward an understanding of the molecular features that define this response, we applied an integrated, multiplatform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted an isoform of phosphoinositide-3-kinase, phosphoinositide-3-kinase gamma isoform (PI3Kγ), by pharmacologic inhibition or genetic inactivation disrupted this signaling axis by reducing microglia/macrophage-associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3Kγ inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3Kγ in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3Kγ inhibition as a glioblastoma therapy.

中文翻译：

PI3K{gamma} 抑制可抑制胶质母细胞瘤微环境中的小胶质细胞/TAM 积累，从而促进异常的替莫唑胺反应 [医学科学]

肿瘤学中的精准医学利用了异常反应的临床观察。为了了解定义这种反应的分子特征，我们对来自临床注释的胶质母细胞瘤样本的 RNA 图谱进行了集成、多平台分析。该分析表明，来自特殊反应者的标本的特征是胶质母细胞瘤微环境中小胶质细胞/巨噬细胞的积累减少。胶质母细胞瘤相关的小胶质细胞/巨噬细胞分泌白细胞介素 11 (IL11) 以激活胶质母细胞瘤细胞中的 STAT3-MYC 信号传导。这种信号诱导干细胞状态，增强致瘤性和对标准化疗替莫唑胺 (TMZ) 的抵抗力。靶向骨髓细胞，通过药理抑制或基因失活，限制磷酸肌醇 3 激酶亚型，磷酸肌醇 3 激酶 γ 亚型 (PI3Kγ)，通过减少肿瘤微环境中小胶质细胞/巨噬细胞相关的 IL11 分泌，破坏该信号轴。与特殊反应者的临床结果相似，PI3Kγ 抑制可协同增强 TMZ 在原位小鼠胶质母细胞瘤模型中的抗肿瘤作用。此外，小鼠胶质母细胞瘤模型中 PI3Kγ 的抑制或基因失活重现了从特殊反应者分离的临床标本中观察到的表达谱。我们的结果表明肿瘤相关小胶质细胞/巨噬细胞在异常反应中的关键贡献，并强调了 PI3Kγ 抑制作为胶质母细胞瘤治疗的转化潜力。

更新日期：2021-04-13

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