The roles of TGF-β and VEGF pathways in the suppression of antitumor immunity in melanoma and other solid tumors

Melissa T Bu; Pallavi Chandrasekhar; Lizhong Ding; Willy Hugo

doi:10.1016/j.pharmthera.2022.108211

The roles of TGF-β and VEGF pathways in the suppression of antitumor immunity in melanoma and other solid tumors

Pharmacol Ther. 2022 Dec:240:108211. doi: 10.1016/j.pharmthera.2022.108211. Epub 2022 May 14.

Authors

Melissa T Bu¹, Pallavi Chandrasekhar², Lizhong Ding³, Willy Hugo⁴

Affiliations

¹ 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.
² 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.
³ Department of Medicine/Dermatology, University of California Los Angeles, Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy UCLA, USA; David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁴ Department of Medicine/Dermatology, University of California Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy UCLA, USA; David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA. Electronic address: hwilly@mednet.ucla.edu.

Abstract

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.

Keywords: Angiogenesis; Bispecific antibody; Combination immunotherapy; Fibrosis; Immunosuppressive tumor microenvironment; Immunotherapy resistance; Trap antibody; Wound healing.

Publication types

Review
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Antibodies
Humans
Immunotherapy / methods
Melanoma* / drug therapy
Neoplasms* / therapy
Programmed Cell Death 1 Receptor
Transforming Growth Factor beta
Tumor Microenvironment
Vascular Endothelial Growth Factor A

Substances

Programmed Cell Death 1 Receptor
Transforming Growth Factor beta
Vascular Endothelial Growth Factor A
Antibodies

Grants and funding

R01 CA236910/CA/NCI NIH HHS/United States