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Durable antitumor responses to CD47 blockade require adaptive immune stimulation

Jonathan T Sockolosky1, Michael Dougan2, Jessica R Ingram3

  • 1Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305;

Proceedings of the National Academy of Sciences of the United States of America
|April 20, 2016
PubMed

Insights

Blocking CD47 alone or with antitumor antibodies failed to generate immunity in mice. Durable tumor immunity required combining programmed death-ligand 1 (PD-L1) blockade with antitumor antibodies, with CD47 antagonism improving responses.

Area of Science:

  • Immunology
  • Cancer Biology
  • Pharmacology

Background:

  • Therapeutic antitumor antibodies leverage innate and adaptive immunity against cancer.
  • Tumor cells use the CD47-signal regulatory protein alpha (SIRPα) axis to evade immune responses.
  • CD47 blockade enhances antibody-dependent cellular phagocytosis (ADCP) in xenografts, but its efficacy in immunocompetent hosts is unclear.

Purpose of the Study:

  • To investigate the efficacy of CD47 blockade as an adjuvant therapy for antitumor antibodies in immunocompetent hosts.
  • To determine the role of innate and adaptive immunity in response to CD47-targeted therapies.
  • To identify optimal combination strategies for potentiating antitumor antibody efficacy.

Main Methods:

  • Utilized syngeneic B16F10 tumor models in mice.
  • Administered CD47 blockade, tumor-specific monoclonal antibodies, and programmed death-ligand 1 (PD-L1) blockade in various combinations.
  • Assessed tumor growth, immune cell infiltration, and development of durable antitumor immunity.

Main Results:

  • CD47 blockade alone or with antitumor antibodies did not induce significant antitumor immunity in syngeneic mouse models.
  • Combination therapy involving PD-L1 blockade and an antitumor antibody was required for durable tumor immunity.
  • Incorporating CD47 antagonism into the PD-L1 blockade and antitumor antibody combination substantially improved response rates.

Conclusions:

  • The adaptive immune system plays a critical, underappreciated role in the efficacy of anti-CD47 adjuvant therapy.
  • Targeting both innate (CD47) and adaptive (PD-L1) immune checkpoints is crucial for potentiating antitumor antibody therapy.
  • Combination immunotherapies that engage both innate and adaptive immunity hold promise for enhancing cancer treatment outcomes.
Keywords:
T cellcancerimmunotherapymacrophageprotein engineering

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