Durable antitumor responses to CD47 blockade require adaptive immune stimulation
Open accessAbstract
Significance: Therapeutic antitumor antibodies are widely used clinically. CD47 is an antiphagocytic ligand expressed by tumors that binds the inhibitory receptor signal regulatory protein alpha (SIRPα) on phagocytic cells. Interruption of CD47–SIRPα interactions in immunodeficient mice bearing human tumors enhances therapeutic antitumor antibody responses by promoting phagocytosis of antibody-bound tumor cells. Here, we use a novel anti-CD47 single domain antibody, derived from an alpaca, in an immunocompetent mouse model of melanoma and find that, in contrast to immunodeficient models, CD47 blockade alone is insufficient to enhance the effects of antimelanoma antibodies. However, when combined with blockade of programmed death-ligand 1 (PD-L1), an immune receptor that inhibits antitumor T cell responses, we find synergistic activity, suggesting a role for both innate and adaptive inhibitory pathways in the response to therapeutic antibodies.
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CD47 antagonizes surface CALR by inhibiting phagocytosis by DCs and macrophages via SIRPA.
“Of note, in some preclinical and clinical instances, the activity of surface-exposed CALR is antagonized by CD47, which operates as a “don’t eat me” signal as it inhibits phagocytosis by DCs and macrophages upon interaction with signal regulatory protein alpha (SIRPA) [885, 886].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [886]
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- Authors
- Sockolosky, J. T., Dougan, M., Ingram, J. R., Ho, C. C. M., Kauke, M. J., Almo, S. C., Ploegh, H. L., & Garcia, K. C.
- Affiliations
- Stanford Medicine (US)
- Massachusetts General Hospital (US)
- Whitehead Institute for Biomedical Research (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- Albert Einstein College of Medicine (US)
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305;
- Corresponding author
- Ploegh, Hidde L.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-04-18
- Volume
- 113
- Issue
- 19
- Pages
- E2646-54
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4868409
- OpenAlex
- W2339658610
- Cited by
- 366
- References
- 47
- Citations by year
- 2026: 22 · 2025: 28 · 2024: 34 · 2023: 56 · 2022: 49 · 2021: 43 · 2020: 37 · 2019: 37 · 2018: 31 · 2017: 24 · 2016: 5
- FWCI
- 19.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- NIH (R01 CA177684, 5T32 AI072905, T32 DK007191)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- CD47 blockade, SIRPα, adaptive immunity, PD-L1 blockade, anti-tumor antibodies, antibody-dependent cellular phagocytosis, macrophages, B16F10 melanoma, adjuvant therapy, antitumor immunity
- MeSH terms
- Animals, Antineoplastic Agents, Female, Immunization, Male, Mice, Inbred C57BL, Neoplasms, Experimental, Treatment Outcome, Cancer Vaccines, Mice, CD47 Antigen, Adaptive Immunity, Antibodies, Monoclonal, Murine-Derived, Molecular Targeted Therapy
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