Mechanisms of PD-L1 Regulation in Malignant and Virus-Infected Cells
Hadia Farrukh1, Nader El-Sayes2, Karen Mossman3
1School of Interdisciplinary Science, Faculty of Science, McMaster University, Hamilton, ON L8S 4K1, Canada.
Abstract:
Programmed cell death protein 1 (PD-1), a receptor on T cells, and its ligand, PD-L1, have been a topic of much interest in cancer research. Both tumour and virus-infected cells can upregulate PD-L1 to suppress cytotoxic T-cell killing. Research on the PD-1/PD-L1 axis has led to the development of anti-PD-1/PD-L1 immune checkpoint blockades (ICBs) as promising cancer therapies. Although effective in some cancer patients, for many, this form of treatment is ineffective due to a lack of immunogenicity in the tumour microenvironment (TME). Despite the development of therapies targeting the PD-1/PD-L1 axis, the mechanisms and pathways through which these proteins are regulated are not completely understood. In this review, we discuss the latest research on molecules of inflammation and innate immunity that regulate PD-L1 expression, how its expression is regulated during viral infection, and how it is modulated by different cancer therapies. We also highlight existing research on the development of different combination therapies with anti-PD-1/PD-L1 antibodies. This information can be used to develop better cancer immunotherapies that take into consideration the pathways involved in the PD-1/PD-L1 axis, so these molecules do not reduce their efficacy, which is currently seen with some cancer therapies. This review will also assist in understanding how the TME changes during treatment, which will provide further rationale for combination therapies.
Insights
Programmed cell death protein 1 (PD-1) and its ligand PD-L1 are key in cancer immunity. Understanding their regulation is crucial for improving anti-PD-1/PD-L1 immunotherapies and overcoming treatment resistance.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Programmed cell death protein 1 (PD-1) and its ligand PD-L1 are critical regulators of T cell responses.
- Upregulation of PD-L1 by tumor cells and virus-infected cells can inhibit anti-tumor immunity.
- Immune checkpoint blockades (ICBs) targeting the PD-1/PD-L1 axis are established cancer therapies, but efficacy is limited in many patients.
Purpose of the Study:
- To review current understanding of PD-L1 regulation by inflammatory and innate immune molecules.
- To explore PD-L1 regulation during viral infections and its modulation by cancer therapies.
- To identify strategies for developing more effective combination immunotherapies targeting the PD-1/PD-L1 axis.
Main Methods:
- Literature review of recent research on PD-1/PD-L1 axis regulation.
- Analysis of studies on inflammation, innate immunity, viral infection, and cancer therapies impacting PD-L1.
- Examination of research on combination therapies involving anti-PD-1/PD-L1 antibodies.
Main Results:
- PD-L1 expression is modulated by various inflammatory and innate immune pathways.
- Viral infections influence PD-L1 regulation, impacting immune evasion.
- Different cancer therapies differentially affect PD-L1 expression and the tumor microenvironment (TME).
Conclusions:
- A comprehensive understanding of PD-L1 regulation is essential for enhancing anti-PD-1/PD-L1 therapy efficacy.
- Targeting PD-L1 regulation pathways may overcome resistance and improve patient outcomes.
- Further research into combination therapies is warranted to optimize cancer immunotherapy.
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