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Regulation of PD-1/PD-L1 pathway and resistance to PD-1/PD-L1 blockade
Jie Bai1, Zhitao Gao1, Xiang Li1
1Department of Molecular Biology and Bio-Therapeutic, School of Life Science, Chinese PLA General Hospital, Beijing 100853, China.
Abstract:
Immune checkpoint blockades, such as inhibitors against programmed death 1 (PD-1) and its ligand (PD-L1), have received extensive attention in the past decade because of their dramatic clinical outcomes in advanced malignancies. However, both primary and acquired resistance becomes one of the major obstacles, which greatly limits the long-lasting effects and wide application of PD-1/PD-L1 blockade therapy. PD-1/PD-L1 both regulates and is regulated by cellular signaling pathways and epigenetic modification, thus inhibiting the proliferation and effector function of T and B cells. The lack of tumor antigens and effective antigen presentation, aberrant activation of oncogenic pathways, mutations in IFN-γ signaling, immunosuppressive tumor microenvironment such as regulatory T cells, myeloid-derived suppressor cells, M2 macrophages, and immunoinhibitory cytokines can lead to resistance to PD-1/PD-L1 blockade. In this review, we describe PD-1 related signaling pathways, essential factors contributing to the resistance of PD-1 blockade, and discuss strategies to increase the efficacy of immunotherapy. Furthermore, we discuss the possibility of combined epigenetic therapy with PD-1 blockade as a potential promising approach for cancer treatment.
Insights
Immune checkpoint inhibitors targeting programmed death 1 (PD-1) and its ligand (PD-L1) show promise but face resistance. Strategies to overcome resistance, including epigenetic therapy, are crucial for enhancing cancer immunotherapy efficacy.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Immune checkpoint inhibitors (ICIs), particularly those targeting programmed death 1 (PD-1) and its ligand (PD-L1), have revolutionized advanced cancer treatment.
- Despite significant clinical success, primary and acquired resistance to PD-1/PD-L1 blockade limits their long-term efficacy and broad application.
Purpose of the Study:
- To review the signaling pathways regulated by PD-1/PD-L1.
- To identify key factors contributing to resistance against PD-1/PD-L1 blockade therapy.
- To discuss strategies for improving immunotherapy outcomes.
Main Methods:
- Literature review of PD-1/PD-L1 signaling pathways.
- Analysis of resistance mechanisms in PD-1/PD-L1 blockade.
- Exploration of therapeutic strategies to enhance ICI efficacy.
Main Results:
- Resistance to PD-1/PD-L1 blockade is multifactorial, involving tumor antigen issues, oncogenic pathway activation, IFN-γ signaling defects, and an immunosuppressive tumor microenvironment (e.g., regulatory T cells, myeloid-derived suppressor cells, M2 macrophages).
- PD-1/PD-L1 signaling is intricately linked with cellular signaling and epigenetic modifications.
Conclusions:
- Understanding the mechanisms of resistance is essential for developing effective cancer immunotherapies.
- Combination strategies, such as epigenetic therapy with PD-1/PD-L1 blockade, hold significant potential for overcoming resistance and improving patient outcomes in advanced malignancies.
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