Positron Emission Tomography Imaging of Functional Transforming Growth Factor β (TGFβ) Activity and Benefit of TGFβ Inhibition in Irradiated Intracranial Tumors.
Positron Emission Tomography Imaging of Functional Transforming Growth Factor β (TGFβ) Activity and Benefit of TGFβ Inhibition in Irradiated Intracranial Tumors.
复制标题
功能转化生长因子β（TGFβ）活性的正电子发射断层扫描成像和TGFβ在辐照颅内肿瘤中的益处。
DOI：
10.1016/j.ijrobp.2020.09.043
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发表时间：
2021-02-01
期刊：
影响因子：
--
通讯作者：
Barcellos-Hoff MH
中科院分区：
文献类型：
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作者：
Gonzalez-Junca A;Reiners O;Borrero-Garcia LD;Beckford-Vera D;Lazar AA;Chou W;Braunstein S;VanBrocklin H;Franc BL;Barcellos-Hoff MH
转化生长因子β（TGFβ）通过支持DNA损伤修复促进细胞存活，并介导免疫抑制性肿瘤微环境。因此，响应于放射疗法的TGFβ活化是潜在可靶向的，因为其对抗治疗控制。需要在临床上评估这种潜力的策略。我们评估了正电子发射断层扫描（PET）对89 Zr-fresolimumab（一种人源化TGFβ中和单克隆抗体）成像，作为检测颅内肿瘤模型中TGFβ活化的手段。TGFβ通路活性通过磷酸化SMAD 2和TGFβ靶标腱生蛋白的免疫检测来验证。通过Kaplan Meier生存分析评估TGFβ对放射反应的贡献，该分析对携带颅内鼠肿瘤模型、GL 261和SB 28胶质母细胞瘤以及脑适应性4 T1乳腺癌（4 T1-BrA）的小鼠进行了TGFβ中和单克隆抗体1D 11和/或局灶性放射（10戈伊）治疗。89 Zr-fresolimumab PET成像检测到工程化的、生理性的和辐射诱导的TGFβ活化，这通过生物标志物的免疫染色来证实。与相似大小的SB 28胶质母细胞瘤肿瘤相比，GL 261胶质母细胞瘤肿瘤具有更多的PET信号，而4 T1-BrA颅内肿瘤的广泛PET信号与其高度分散的组织学分布一致。单独用1D 11中和抗体处理的携带颅内肿瘤的小鼠的存活率与用对照抗体处理的小鼠的存活率相似，而当与局灶性放射组合给予时，1D 11改善了存活率。放疗和1D 11联合治疗的生存获益程度与PET检测到的TGFβ活性程度相关。该研究表明，89 Zr-fresolimumab PET成像检测肿瘤中辐射诱导的TGFβ活化。功能成像显示颅内肿瘤中存在一系列TGFβ活性，但TGFβ阻断剂仅在放射治疗的背景下提供生存益处。这些研究进一步证明，辐射诱导的TGFβ活性对抗对辐射的治疗反应。
Transforming growth factor β (TGFβ) promotes cell survival by endorsing DNA damage repair and mediates an immunosuppressive tumor microenvironment. Thus, TGFβ activation in response to radiation therapy is potentially targetable because it opposes therapeutic control. Strategies to assess this potential in the clinic are needed. We evaluated positron emission tomography (PET) to image 89Zr -fresolimumab, a humanized TGFβ neutralizing monoclonal antibody, as means to detect TGFβ activation in intracranial tumor models. TGFβ pathway activity was validated by immunodetection of phosphorylated SMAD2 and TGFβ target, tenascin. The contribution of TGFβ to radiation response was assessed by Kaplan Meier survival analysis of mice bearing intracranial murine tumor models, GL261 and SB28 glioblastoma and brain-adapted 4T1 breast cancer (4T1-BrA) treated with TGFβ neutralizing monoclonal antibody, 1D11, and/or focal radiation (10 Gy). 89Zr-fresolimumab PET imaging detected engineered, physiological and radiation-induced TGFβ activation, which was confirmed by immunostaining of biological markers. GL261 glioblastoma tumors had more PET signal compared to similar sized SB28 glioblastoma tumors, whereas widespread PET signal of 4T1-BrA intracranial tumors is consistent with its highly dispersed histological distribution. Survival of mice bearing intracranial tumors treated with 1D11 neutralizing antibody alone was similar to that of mice treated with control antibody whereas 1D11 improved survival when given in combination with focal radiation. The extent of survival benefit of combination of radiation and 1D11 was associated with the degree of TGFβ activity detected by PET. This study demonstrates that 89Zr -fresolimumab PET imaging detects radiation-induced TGFβ activation in tumors. Functional imaging indicated a range of TGFβ activity in intracranial tumors, but TGFβ blockade provided survival benefit only in the context of radiation treatment. These studies are further evidence that radiation-induced TGFβ activity opposes therapeutic response to radiation.