Acquired Resistance to PD-1/PD-L1 Blockade in Lung Cancer: Mechanisms and Patterns of Failure
Abstract
:Simple Summary
Abstract
1. Introduction
2. PD-1/PD-L1 Axis in Normal Health and Tumorigenesis
3. Mechanisms of Acquired ICI Resistance
3.1. Impaired T Cell Activation
3.1.1. Loss of Antigen Presentation
3.1.2. Fixed Epigenetic Modification and Lack of Memory T Cells
3.2. Impaired T Cell Effector Functions
3.2.1. Defects of Interferon Pathways
3.2.2. Upregulation of Other Immune Checkpoints
3.2.3. Altered Metabolism and Suppressive Metabolites
3.3. Other Local Immunosuppressive Factors within the TME
3.4. Role of Host Factors in ICI Resistance
4. Patterns of Failures After PD-1/PD-L1 Blockade
5. Principles of Overcoming Acquired Resistance to PD-1/PD-L1 Blockade
6. Conclusions and Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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Mechanisms of Acquired ICI Resistance | Potential Therapeutic Approaches |
---|---|
Impaired processing or presentation of tumor-associated antigens | Chemotherapy, radiotherapy, cancer vaccines, oncolytic viruses, TLR agonists |
Fixed epigenetic modification of T cells | Epigenetic modulators (hypomethylating agents, histone deacetylase inhibitors) |
Defects in IFN-γ pathways | STING agonists, c-di-GMP, JAK inhibitors |
Upregulation of other immune checkpoints | Combination immune checkpoint inhibitors (such as CTLA-4, TIGIT, LAG-3, TIM-3, VISTA, BTLA), immune stimulatory agents (such as OX40, CD40, GITR, ICOS, 4-1BB) |
Immunosuppressive cells/inhibitory metabolites in the tumor microenvironment | Macrophage inhibitors (such as CSF1R inhibitors), cytokine/chemokine inhibitors, targeted therapies targeting canonical pathways (such as against VEGF, PI3K), IDO inhibitors, TGF-β inhibitors, CXCR2 inhibitors, CXCR4 inhibitors, A2AR inhibitors/anti-CD73 |
Gut microbiome | Fecal microbiota transplantation, probiotics, diet interventions |
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Pathak, R.; Pharaon, R.R.; Mohanty, A.; Villaflor, V.M.; Salgia, R.; Massarelli, E. Acquired Resistance to PD-1/PD-L1 Blockade in Lung Cancer: Mechanisms and Patterns of Failure. Cancers 2020, 12, 3851. https://doi.org/10.3390/cancers12123851
Pathak R, Pharaon RR, Mohanty A, Villaflor VM, Salgia R, Massarelli E. Acquired Resistance to PD-1/PD-L1 Blockade in Lung Cancer: Mechanisms and Patterns of Failure. Cancers. 2020; 12(12):3851. https://doi.org/10.3390/cancers12123851
Chicago/Turabian StylePathak, Ranjan, Rebecca R. Pharaon, Atish Mohanty, Victoria M. Villaflor, Ravi Salgia, and Erminia Massarelli. 2020. "Acquired Resistance to PD-1/PD-L1 Blockade in Lung Cancer: Mechanisms and Patterns of Failure" Cancers 12, no. 12: 3851. https://doi.org/10.3390/cancers12123851