Related Experiment Video
Updated: Feb 23, 2026
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
Localized CD47 blockade enhances immunotherapy for murine melanoma
Jessica R Ingram1,2, Olga S Blomberg1, Jonathan T Sockolosky3,4
1Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142.
Abstract:
CD47 is an antiphagocytic ligand broadly expressed on normal and malignant tissues that delivers an inhibitory signal through the receptor signal regulatory protein alpha (SIRPα). Inhibitors of the CD47-SIRPα interaction improve antitumor antibody responses by enhancing antibody-dependent cellular phagocytosis (ADCP) in xenograft models. Endogenous expression of CD47 on a variety of cell types, including erythrocytes, creates a formidable antigen sink that may limit the efficacy of CD47-targeting therapies. We generated a nanobody, A4, that blocks the CD47-SIRPα interaction. A4 synergizes with anti-PD-L1, but not anti-CTLA4, therapy in the syngeneic B16F10 melanoma model. Neither increased dosing nor half-life extension by fusion of A4 to IgG2a Fc (A4Fc) overcame the issue of an antigen sink or, in the case of A4Fc, systemic toxicity. Generation of a B16F10 cell line that secretes the A4 nanobody showed that an enhanced response to several immune therapies requires near-complete blockade of CD47 in the tumor microenvironment. Thus, strategies to localize CD47 blockade to tumors may be particularly valuable for immune therapy.
Insights
Blocking CD47, a protein on cancer cells, can boost immune responses. Localizing this blockade to tumors is key for effective cancer immunotherapy, overcoming challenges like antigen sinks.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- CD47 is an antiphagocytic ligand on normal and malignant cells, inhibiting immune responses via SIRPα.
- CD47 inhibitors enhance anti-tumor antibody responses by promoting phagocytosis in models.
- Widespread CD47 expression, especially on erythrocytes, acts as an antigen sink, potentially limiting therapy efficacy.
Purpose of the Study:
- To develop a nanobody (A4) targeting the CD47-SIRPα interaction.
- To evaluate A4's efficacy alone and in combination with immunotherapies in a syngeneic melanoma model.
- To investigate strategies for overcoming CD47-related challenges in cancer immunotherapy.
Main Methods:
- Generation of a nanobody (A4) that blocks CD47-SIRPα interaction.
- Assessment of A4 in combination with anti-PD-L1 and anti-CTLA4 therapies in B16F10 melanoma models.
- Development of a B16F10 cell line secreting A4 to achieve localized CD47 blockade.
Main Results:
- A4 synergized with anti-PD-L1 but not anti-CTLA4 therapy.
- Increased dosing or Fc-fusion of A4 did not overcome the antigen sink issue or systemic toxicity.
- Localized CD47 blockade via A4 secretion from tumor cells enhanced immune responses.
Conclusions:
- Near-complete CD47 blockade within the tumor microenvironment is crucial for enhancing immune therapies.
- Strategies focusing on localized CD47 blockade may overcome limitations of systemic approaches.
- Targeting the CD47-SIRPα axis holds promise for improving cancer immunotherapy outcomes.
