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Published on: May 2, 2025
Combination Approaches to Target PD-1 Signaling in Cancer
Emily K Moore1,2, Marianne Strazza1,2, Adam Mor1,2,3
1Division of Rheumatology, Department of Medicine, Columbia University Medical Center, New York, NY, United States.
Abstract:
Cancer remains the second leading cause of death in the US, accounting for 25% of all deaths nationwide. Immunotherapy techniques bolster the immune cells' ability to target malignant cancer cells and have brought immense improvements in the field of cancer treatments. One important inhibitory protein in T cells, programmed cell death protein 1 (PD-1), has become an invaluable target for cancer immunotherapy. While anti-PD-1 antibody therapy is extremely successful in some patients, in others it fails or even causes further complications, including cancer hyper-progression and immune-related adverse events. Along with countless translational studies of the PD-1 signaling pathway, there are currently close to 5,000 clinical trials for antibodies against PD-1 and its ligand, PD-L1, around 80% of which investigate combinations with other therapies. Nevertheless, more work is needed to better understand the PD-1 signaling pathway and to facilitate new and improved evidence-based combination strategies. In this work, we consolidate recent discoveries of PD-1 signaling mediators and their therapeutic potential in combination with anti-PD-1/PD-L1 agents. We focus on the phosphatases SHP2 and PTPN2; the kinases ITK, VRK2, GSK-3, and CDK4/6; and the signaling adaptor protein PAG. We discuss their biology both in cancer cells and T cells, with a focus on their role in relation to PD-1 to determine their potential in therapeutic combinations. The literature discussed here was obtained from a search of the published literature and ClinicalTrials.gov with the following key terms: checkpoint inhibition, cancer immunotherapy, PD-1, PD-L1, SHP2, PTPN2, ITK, VRK2, CDK4/6, GSK-3, and PAG. Together, we find that all of these proteins are logical and promising targets for combination therapy, and that with a deeper mechanistic understanding they have potential to improve the response rate and decrease adverse events when thoughtfully used in combination with checkpoint inhibitors.
Insights
Cancer immunotherapy using anti-PD-1 antibodies shows promise but has limitations. This study explores novel combination strategies targeting PD-1 signaling mediators to improve treatment efficacy and reduce adverse events in cancer patients.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Cancer immunotherapy, particularly targeting programmed cell death protein 1 (PD-1), has revolutionized cancer treatment.
- Despite successes, anti-PD-1 antibody therapy faces challenges including treatment failure, hyper-progression, and immune-related adverse events in some patients.
- Understanding the PD-1 signaling pathway is crucial for developing improved and evidence-based combination strategies.
Purpose of the Study:
- To consolidate recent discoveries in PD-1 signaling mediators.
- To evaluate the therapeutic potential of these mediators in combination with anti-PD-1/PD-L1 agents.
- To identify new targets for enhancing cancer immunotherapy.
Main Methods:
- Literature review focusing on PD-1 signaling pathway mediators.
- Analysis of the biological roles of specific proteins (SHP2, PTPN2, ITK, VRK2, GSK-3, CDK4/6, PAG) in cancer and T cells.
- Exploration of their potential in combination therapies with checkpoint inhibitors.
Main Results:
- Identified phosphatases (SHP2, PTPN2), kinases (ITK, VRK2, GSK-3, CDK4/6), and adaptor protein (PAG) as key PD-1 signaling mediators.
- These proteins play significant roles in both cancer cells and T cells, influencing the efficacy of PD-1 blockade.
- All discussed proteins demonstrate potential as logical targets for combination therapy.
Conclusions:
- Targeting PD-1 signaling mediators offers a promising avenue for improving cancer immunotherapy.
- Combination strategies involving these mediators and checkpoint inhibitors have the potential to increase response rates.
- Further mechanistic understanding of these targets can lead to reduced adverse events and enhanced therapeutic outcomes.
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