Department of Medicine/Dermatology, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA.
Department of Medicine/Dermatology, University of California Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA.
Pharmacol Ther. 2022 Dec;240:108211. doi: 10.1016/j.pharmthera.2022.108211. Epub 2022 May 14.
Immune checkpoint blockade (ICB) has become well-known in cancer therapy, strengthening the body's antitumor immune response rather than directly targeting cancer cells. Therapies targeting immune inhibitory checkpoints, such as PD-1, PD-L1, and CTLA-4, have resulted in impressive clinical responses across different types of solid tumors. However, as with other types of cancer treatments, ICB-based immunotherapy is hampered by both innate and acquired drug resistance. We previously reported the enrichment of gene signatures associated with wound healing, epithelial-to-mesenchymal, and angiogenesis processes in the tumors of patients with innate resistance to PD-1 checkpoint antibody therapy; we termed these the Innate Anti-PD-1 Resistance Signatures (IPRES). The TGF-β and VEGFA pathways emerge as the dominant drivers of IPRES-associated processes. Here, we review these pathways' functions, their roles in immunosuppression, and the currently available therapies that target them. We also discuss recent developments in the targeting of TGF-β using a specific antibody class termed trap antibody. The application of trap antibodies opens the promise of localized targeting of the TGF-β and VEGFA pathways within the tumor microenvironment. Such specificity may offer an enhanced therapeutic window that enables suppression of the IPRES processes in the tumor microenvironment while sparing the normal homeostatic functions of TGF-β and VEGFA in healthy tissues.
免疫检查点阻断（ICB）在癌症治疗中已经广为人知，它增强了身体的抗肿瘤免疫反应，而不是直接针对癌细胞。针对免疫抑制检查点的疗法，如 PD-1、PD-L1 和 CTLA-4，已在不同类型的实体瘤中产生了令人印象深刻的临床反应。然而，与其他类型的癌症治疗一样，基于 ICB 的免疫疗法也受到固有和获得性耐药性的阻碍。我们之前报道了在对 PD-1 检查点抗体治疗具有固有耐药性的患者的肿瘤中，与伤口愈合、上皮间质转化和血管生成过程相关的基因特征的富集；我们将这些特征称为固有抗 PD-1 耐药特征（IPRES）。TGF-β和 VEGFA 途径成为 IPRES 相关过程的主要驱动因素。在这里，我们回顾了这些途径的功能、它们在免疫抑制中的作用以及目前针对它们的治疗方法。我们还讨论了使用称为陷阱抗体的特定抗体类别靶向 TGF-β 的最新进展。陷阱抗体的应用为在肿瘤微环境中靶向 TGF-β 和 VEGFA 途径提供了前景。这种特异性可能提供一个增强的治疗窗口，在抑制肿瘤微环境中的 IPRES 过程的同时，保留 TGF-β 和 VEGFA 在健康组织中的正常动态平衡功能。
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