Landscape of surfaceome and endocytome in human glioma is divergent and depends on cellular spatial organization.
Landscape of surfaceome and endocytome in human glioma is divergent and depends on cellular spatial organization.
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DOI：
10.1073/pnas.2114456119
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发表时间：
2022-03-01
影响因子：
11.1
通讯作者：
Belting M
中科院分区：
文献类型：
--
作者：
Governa V;Talbot H;Gonçalves de Oliveira K;Cerezo-Magaña M;Bång-Rudenstam A;Johansson MC;Månsson AS;Forsberg-Nilsson K;Marko-Varga G;Enríquez Pérez J;Darabi A;Malmström J;Bengzon J;Welinder C;Belting M
癌症免疫疗法，包括检查点抑制剂阻断抗体和抗体药物缀合物，目前正在彻底改变癌症治疗。然而，剩下的挑战是识别肿瘤表面组（TS）靶点，以设计更合理的个体化治疗。我们已经开发了一种用于胶质母细胞瘤（GBM）中TS靶点的无偏映射的程序，即，这是最常见的原发性恶性脑肿瘤，仍然是最具侵袭性的癌症之一，迄今为止，寻找有效治疗方法的尝试都失败了。本研究为免疫治疗策略的未来发展提供了额外的理解层，以及基于蛋白质组学的靶点识别程序，旨在更好地了解如何利用TS进行个性化免疫治疗。针对肿瘤表面组（TS）的治疗策略，包括检查点抑制剂阻断抗体、抗体药物缀合物（ADC）和嵌合抗原受体T（CAR-T）细胞，提供了对抗癌症的新武器。然而，剩余的瓶颈是缺乏全面询问患者肿瘤的潜在TS靶标的策略。在这里，我们开发了一个平台（肿瘤表面组映射[TS-MAP]），与新策划的TS分类器（SURFME）集成，允许对原代3D培养物和具有保留组织结构的完整患者胶质瘤肿瘤进行分析。此外，TS-MAP特异性地鉴定能够内吞作用的蛋白质作为ADC和需要毒性有效负载内化的其他模式的易处理靶标。在仍然是最具侵袭性的癌症形式之一的高级别胶质瘤中，我们表明细胞空间组织（2D与3D）从根本上改变了表面组和胞内组（例如，整联蛋白、蛋白聚糖、信号蛋白和癌症干细胞标志物），其对于靶筛选方法具有一般意义，如靶向EGFR的ADC所例示。TS-MAP平台进一步应用于描绘一组新鲜切除的胶质瘤中的表面组和胞内组景观。我们发现患者肿瘤之间存在高度多样的TS库，与分级和组织学无直接关系，这突出了个体化方法的必要性。我们的数据为免疫治疗策略的未来发展以及基于蛋白质组学的靶点识别和选择程序提供了额外的理解层。TS-MAP平台应广泛适用于旨在更好地了解如何利用TS进行个性化免疫治疗的努力。
Cancer immunotherapies, including checkpoint inhibitor blocking antibodies and antibody drug conjugates, currently revolutionize cancer treatment. However, a remaining challenge is the identification of tumor surfaceome (TS) targets for the design of more rational, individualized treatments. We have developed a procedure for unbiased mapping of TS targets in glioblastoma (GBM), i.e., the most common primary malignant brain tumor that remains among the most aggressive forms of cancer, and for which attempts to find effective treatments have failed so far. The present study provides additional layers of understanding fundamental to the future development of immunotherapy strategies, as well as procedures for proteomics-based target identification aimed at a better understanding of how to harness the TS for personalized immunotherapy. Therapeutic strategies directed at the tumor surfaceome (TS), including checkpoint inhibitor blocking antibodies, antibody drug conjugates (ADCs), and chimeric antigen receptor T (CAR-T) cells, provide a new armament to fight cancer. However, a remaining bottleneck is the lack of strategies to comprehensively interrogate patient tumors for potential TS targets. Here, we have developed a platform (tumor surfaceome mapping [TS-MAP]) integrated with a newly curated TS classifier (SURFME) that allows profiling of primary 3D cultures and intact patient glioma tumors with preserved tissue architecture. Moreover, TS-MAP specifically identifies proteins capable of endocytosis as tractable targets for ADCs and other modalities requiring toxic payload internalization. In high-grade gliomas that remain among the most aggressive forms of cancer, we show that cellular spatial organization (2D vs. 3D) fundamentally transforms the surfaceome and endocytome (e.g., integrins, proteoglycans, semaphorins, and cancer stem cell markers) with general implications for target screening approaches, as exemplified by an ADC targeting EGFR. The TS-MAP platform was further applied to profile the surfaceome and endocytome landscape in a cohort of freshly resected gliomas. We found a highly diverse TS repertoire between patient tumors, not directly associated with grade and histology, which highlights the need for individualized approaches. Our data provide additional layers of understanding fundamental to the future development of immunotherapy strategies, as well as procedures for proteomics-based target identification and selection. The TS-MAP platform should be widely applicable in efforts aiming at a better understanding of how to harness the TS for personalized immunotherapy.
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DOI：
10.1073/pnas.1808790115
发表时间：
2018-11-13
影响因子：
11.1
作者：
Bausch-Fluck D;Goldmann U;Müller S;van Oostrum M;Müller M;Schubert OT;Wollscheid B
通讯作者：
Wollscheid B
影响因子：
23.9
作者：
Haas, Tobias L.;Sciuto, Maria Rita;De Maria, Ruggero
通讯作者：
De Maria, Ruggero
影响因子：
11.1
作者：
Buser, Dominik P.;Ritz, Marie-Francoise;Hutter, Gregor
通讯作者：
Hutter, Gregor
影响因子：
4.4
作者：
Davis, Simon;Scott, Connor;Fischer, Roman
通讯作者：
Fischer, Roman
影响因子：
23.9
作者：
Lathia JD;Gallagher J;Heddleston JM;Wang J;Eyler CE;Macswords J;Wu Q;Vasanji A;McLendon RE;Hjelmeland AB;Rich JN
通讯作者：
Rich JN