Dual inhibition of TGF-β and PD-L1: a novel approach to cancer treatment.
Dual inhibition of TGF-β and PD-L1: a novel approach to cancer treatment.
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DOI：
10.1002/1878-0261.13146
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发表时间：
2022-06
影响因子：
6.6
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中科院分区：
文献类型：
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转化生长因子-β（TGF-β）和程序性死亡配体1（PD - L1）在肿瘤微环境（TME）中启动具有互补、非冗余免疫抑制功能的信号通路。在TME中，失调的TGF-β信号传导抑制抗肿瘤免疫，促进癌症纤维化、上皮 - 间质转化和血管生成。同时，PD - L1的表达使细胞毒性T细胞失活，并限制TME中的免疫监视。抗PD - L1疗法已被批准用于治疗多种癌症，但TME中的TGF-β信号与对这些疗法的耐药性有关。在这篇综述中，我们讨论了TGF-β和PD - L1通路在癌症中的重要性，以及使用分别阻断这些通路的联合疗法或使用双靶向药物（双特异性和双功能免疫疗法）可能同时阻断它们的临床策略。目前，研发进展最快的双靶向药物是bintrafusp alfa。这种药物是一种首创的双功能融合蛋白，由TGF-βRII受体的胞外结构域（一种TGF-β“陷阱”）与人免疫球蛋白G1（IgG1）抗PD - L1单克隆抗体融合而成。鉴于TME中TGF-β和PD - L1通路的免疫抑制作用，对这些通路的共定位和同时抑制可能潜在地提高临床疗效并降低毒性。
TGF-β和PD - L1信号通路在肿瘤微环境中具有互补、非冗余的功能。失调的TGF-β信号传导抑制抗肿瘤免疫，促进癌症纤维化、上皮 - 间质转化和血管生成，而PD - L1限制免疫监视。我们综述了同时抑制这些通路的现有策略，重点介绍了可能提供共定位、同时抑制的双靶向药物。
Transforming growth factor‐β (TGF‐β) and programmed death ligand 1 (PD‐L1) initiate signaling pathways with complementary, nonredundant immunosuppressive functions in the tumor microenvironment (TME). In the TME, dysregulated TGF‐β signaling suppresses antitumor immunity and promotes cancer fibrosis, epithelial‐to‐mesenchymal transition, and angiogenesis. Meanwhile, PD‐L1 expression inactivates cytotoxic T cells and restricts immunosurveillance in the TME. Anti‐PD‐L1 therapies have been approved for the treatment of various cancers, but TGF‐β signaling in the TME is associated with resistance to these therapies. In this review, we discuss the importance of the TGF‐β and PD‐L1 pathways in cancer, as well as clinical strategies using combination therapies that block these pathways separately or approaches with dual‐targeting agents (bispecific and bifunctional immunotherapies) that may block them simultaneously. Currently, the furthest developed dual‐targeting agent is bintrafusp alfa. This drug is a first‐in‐class bifunctional fusion protein that consists of the extracellular domain of the TGF‐βRII receptor (a TGF‐β ‘trap’) fused to a human immunoglobulin G1 (IgG1) monoclonal antibody blocking PD‐L1. Given the immunosuppressive effects of the TGF‐β and PD‐L1 pathways within the TME, colocalized and simultaneous inhibition of these pathways may potentially improve clinical activity and reduce toxicity. The TGF‐β and PD‐L1 signaling pathways have complementary, nonredundant functions in the tumor microenvironment. Dysregulated TGF‐β signaling suppresses antitumor immunity and promotes cancer fibrosis, epithelial–mesenchymal transition, and angiogenesis, while PD‐L1 restricts immunosurveillance. We review existing strategies for simultaneous inhibition of these pathways, highlighting dual‐targeting agents that may provide colocalized, simultaneous inhibition.
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影响因子：
8
作者：
Courau, Tristan;Nehar-Belaid, Djamel;Klatzmann, David
通讯作者：
Klatzmann, David
影响因子：
50.3
作者：
Calon A;Espinet E;Palomo-Ponce S;Tauriello DV;Iglesias M;Céspedes MV;Sevillano M;Nadal C;Jung P;Zhang XH;Byrom D;Riera A;Rossell D;Mangues R;Massagué J;Sancho E;Batlle E
通讯作者：
Batlle E
影响因子：
45.3
作者：
Daud, Adil I.;Wolchok, Jedd D.;Hamid, Omid
通讯作者：
Hamid, Omid
影响因子：
45.3
作者：
De Santis, Maria;Bellmunt, Joaquim;Sylvester, Richard
通讯作者：
Sylvester, Richard
影响因子：
7.2
作者：
David JM;Dominguez C;McCampbell KK;Gulley JL;Schlom J;Palena C
通讯作者：
Palena C