期刊
PHARMACOLOGY & THERAPEUTICS
卷 240, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pharmthera.2022.108211
关键词
Immunosuppressivetumormicroenvironment; Immunotherapyresistance; Trapantibody; Bispecificantibody; Angiogenesis; Woundhealing; Fibrosis; Combinationimmunotherapy
资金
- NIH/NCI grant [1R01CA236910-01]
- Melanoma Research Alliance
- Margaret E. Early Medical Research Trust
- Parker Institute for Cancer Immunotherapy at UCLA
- AMGEN Scholars Program
Immune checkpoint blockade is a well-known approach in cancer therapy, but drug resistance remains a challenge. Gene signatures associated with innate resistance to PD-1 antibody therapy were enriched, with TGF-β and VEGFA pathways identified as dominant drivers. Targeting TGF-β using trap antibodies offers promise for localized therapy within the tumor microenvironment.
Immune checkpoint blockade (ICB) has become well-known in cancer therapy, strengthening the body's antitu-mor immune response rather than directly targeting cancer cells. Therapies targeting immune inhibitory check-points, 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 in-nate resistance to PD-1 checkpoint antibody therapy; we termed these the Innate Anti-PD-1 Resistance Signa-tures (IPRES). The TGF-I3 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 ther-apies that target them. We also discuss recent developments in the targeting of TGF-I3 using a specific antibody class termed trap antibody. The application of trap antibodies opens the promise of localized targeting of the TGF-I3 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 nor-mal homeostatic functions of TGF-I3 and VEGFA in healthy tissues.(c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).
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