CD47: The Next Frontier in Immune Checkpoint Blockade for Non-Small Cell Lung Cancer
Asa P Y Lau1,2, Sharon S Khavkine Binstock1,2, Kelsie L Thu1,2
1Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Abstract:
The success of PD-1/PD-L1-targeted therapy in lung cancer has resulted in great enthusiasm for additional immunotherapies in development to elicit similar survival benefits, particularly in patients who do not respond to or are ineligible for PD-1 blockade. CD47 is an immunosuppressive molecule that binds SIRPα on antigen-presenting cells to regulate an innate immune checkpoint that blocks phagocytosis and subsequent activation of adaptive tumor immunity. In lung cancer, CD47 expression is associated with poor survival and tumors with EGFR mutations, which do not typically respond to PD-1 blockade. Given its prognostic relevance, its role in facilitating immune escape, and the number of agents currently in clinical development, CD47 blockade represents a promising next-generation immunotherapy for lung cancer. In this review, we briefly summarize how tumors disrupt the cancer immunity cycle to facilitate immune evasion and their exploitation of immune checkpoints like the CD47-SIRPα axis. We also discuss approved immune checkpoint inhibitors and strategies for targeting CD47 that are currently being investigated. Finally, we review the literature supporting CD47 as a promising immunotherapeutic target in lung cancer and offer our perspective on key obstacles that must be overcome to establish CD47 blockade as the next standard of care for lung cancer therapy.
Insights
CD47 blockade is a promising immunotherapy for lung cancer, especially for patients unresponsive to PD-1 inhibitors. Targeting the CD47-SIRPα axis can overcome immune evasion and improve survival in lung cancer patients.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Programmed cell death protein 1 (PD-1) and its ligand (PD-L1) therapies have shown success in lung cancer.
- However, many patients do not respond to or are ineligible for PD-1 blockade.
- CD47, an immunosuppressive molecule, is upregulated in lung cancer and associated with poor prognosis, particularly in EGFR-mutated tumors resistant to PD-1 therapy.
Purpose of the Study:
- To review the role of the CD47-SIRPα axis in lung cancer immune evasion.
- To discuss current and emerging CD47-targeting strategies for lung cancer immunotherapy.
- To evaluate CD47 blockade as a potential next-generation lung cancer therapy.
Main Methods:
- Literature review of the cancer immunity cycle and immune checkpoints.
- Analysis of CD47 expression in lung cancer and its correlation with survival and mutations.
- Review of approved immune checkpoint inhibitors and ongoing CD47-targeting clinical trials.
Main Results:
- Tumors disrupt the cancer immunity cycle and exploit immune checkpoints like CD47-SIRPα for immune escape.
- CD47 expression is linked to poor survival in lung cancer, especially in EGFR-mutated tumors.
- Several CD47-targeting agents are in clinical development for lung cancer.
Conclusions:
- CD47 blockade represents a promising next-generation immunotherapy for lung cancer.
- Targeting the CD47-SIRPα axis can overcome innate immune checkpoints and enhance anti-tumor immunity.
- Overcoming obstacles in CD47 blockade development is crucial for establishing it as a standard lung cancer therapy.
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