A fluorogenic probe for granzyme B enables in-biopsy evaluation and screening of response to anticancer immunotherapies.
A fluorogenic probe for granzyme B enables in-biopsy evaluation and screening of response to anticancer immunotherapies.
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DOI：
10.1038/s41467-022-29691-w
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发表时间：
2022-05-02
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
免疫疗法促进免疫系统攻击癌细胞；然而，在肿瘤大小发生变化之前很难检测到早期反应。在这里，我们报告了一种荧光肽的合理设计，该荧光肽能够检测皮摩尔浓度的活性颗粒酶 B，作为免疫介导的抗癌作用的生物标志物。通过一系列化学迭代和分子动力学模拟，我们合成了 FRET 肽库，并鉴定了与颗粒酶 B 最佳匹配的探针 H5。我们证明探针 H5 能够实时检测小鼠肿瘤和肺癌患者肿瘤中 T 细胞介导的抗癌活性。此外，我们还展示了基于图像的表型筛选，结果表明 AKT 激酶抑制剂 AZD5363 显示出免疫介导的抗癌活性。探针 H5 的反应性可以利用组织活检来监测抗癌治疗的早期反应。粒酶 B 存在于活化的 T 细胞中，可用作 T 细胞活化的标志物。在这里，作者生成了一种荧光探针，可以检测肿瘤中的粒酶 B 水平，并有可能用作免疫治疗反应的生物标志物。
Immunotherapy promotes the attack of cancer cells by the immune system; however, it is difficult to detect early responses before changes in tumor size occur. Here, we report the rational design of a fluorogenic peptide able to detect picomolar concentrations of active granzyme B as a biomarker of immune-mediated anticancer action. Through a series of chemical iterations and molecular dynamics simulations, we synthesize a library of FRET peptides and identify probe H5 with an optimal fit into granzyme B. We demonstrate that probe H5 enables the real-time detection of T cell-mediated anticancer activity in mouse tumors and in tumors from lung cancer patients. Furthermore, we show image-based phenotypic screens, which reveal that the AKT kinase inhibitor AZD5363 shows immune-mediated anticancer activity. The reactivity of probe H5 may enable the monitoring of early responses to anticancer treatments using tissue biopsies. Granzyme B is found in activated T cells and can be used as a marker of T cell activation. Here, the authors generate a fluorescent probe that can detect Granzyme B levels in tumours, and has the potential to be used as a biomarker of response to immunotherapy.
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影响因子：
4.8
作者：
Janiszewski, Tomasz;Kolt, Sonia;Kasperkiewicz, Paulina
通讯作者：
Kasperkiewicz, Paulina
影响因子：
15
作者：
Aron AT;Loehr MO;Bogena J;Chang CJ
通讯作者：
Chang CJ
影响因子：
7.7
作者：
Canel, Marta;Taggart, David;Serrels, Alan
通讯作者：
Serrels, Alan
影响因子：
5.5
作者：
Goetz, Andreas W.;Williamson, Mark J.;Xu, Dong;Poole, Duncan;Le Grand, Scott;Walker, Ross C.
通讯作者：
Walker, Ross C.
影响因子：
28.1
作者：
Mac, Quoc D.;Mathews, Dave, V;Kwong, Gabriel A.
通讯作者：
Kwong, Gabriel A.