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Therapeutic modulation of the CD47-SIRPα axis in the pediatric tumor microenvironment: working up an appetite
Ajay Gupta1, Cenny Taslim2, Brian P Tullius1
1Division of Hematology, Oncology, Blood and Marrow Transplant, Nationwide Children's Hospital, Columbus, OH 43205, USA.
Abstract:
Evasion of immune surveillance is one of the hallmarks of cancer. Although the adaptive immune system has been targeted via checkpoint inhibition, many patients do not sustain durable remissions due to the heterogeneity of the tumor microenvironment, so additional strategies are needed. The innate immune system has its own set of checkpoints, and tumors have co-opted this system by expressing surface receptors that inhibit phagocytosis. One of these receptors, CD47, also known as the "don't eat me" signal, has been found to be overexpressed by most cancer histologies and has been successfully targeted by antibodies blocking the receptor or its ligand, signal regulatory protein α (SIRPα). By enabling phagocytosis via antigen-presenting cells, interruption of CD47-SIRPα binding leads to earlier downstream activation of the adaptive immune system. Recent and ongoing clinical trials are demonstrating the safety and efficacy of CD47 blockade in combination with monoclonal antibodies, chemotherapy, or checkpoint inhibitors for adult cancer histologies. The aim of this review is to highlight the current literature and research on CD47, provide an impetus for investigation of its blockade in pediatric cancer histologies, and provide a rationale for new combination therapies in these patients.
Insights
Cancer cells evade immune detection using the "don't eat me" signal, CD47. Blocking CD47 enhances phagocytosis and immune response, showing promise in adult cancers and potential for pediatric applications.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Cancer immune evasion is a major challenge, necessitating novel therapeutic strategies beyond adaptive immune checkpoint inhibition.
- Tumors exploit innate immune checkpoints, such as the CD47 receptor, to inhibit phagocytosis and avoid immune destruction.
- CD47, the "don't eat me" signal, is overexpressed in many cancers, making it a viable therapeutic target.
Purpose of the Study:
- To review current research on CD47 blockade in cancer therapy.
- To explore the potential of CD47 blockade in pediatric cancer histologies.
- To provide a rationale for novel combination therapies involving CD47 blockade.
Main Methods:
- Literature review of existing research on CD47 and its role in cancer immunology.
- Analysis of clinical trial data for CD47 blockade in adult cancer patients.
- Exploration of preclinical data and theoretical frameworks for pediatric applications.
Main Results:
- CD47 blockade, by interrupting the CD47-SIRPα interaction, promotes phagocytosis by antigen-presenting cells.
- Clinical trials indicate safety and efficacy of CD47 blockade in combination regimens for adult cancers.
- CD47 blockade synergizes with monoclonal antibodies, chemotherapy, and checkpoint inhibitors.
Conclusions:
- CD47 blockade represents a promising strategy to overcome cancer immune evasion by reactivating innate and adaptive immunity.
- Further investigation into CD47 blockade is warranted for pediatric cancers, potentially leading to new combination therapies.
- Targeting CD47 offers a pathway to enhance existing cancer treatments and improve patient outcomes.
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