Durable antitumor responses to CD47 blockade require adaptive immune stimulation

Jonathan T. Sockolosky, Michael Dougan, Jessica R. Ingram, Chia Chi M Ho, Monique J. Kauke, Steven C. Almo, Hidde L. Ploegh, K. Christopher Garciaa

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Therapeutic antitumor antibodies treat cancer by mobilizing both innate and adaptive immunity. CD47 is an antiphagocytic ligand exploited by tumor cells to blunt antibody effector functions by transmitting an inhibitory signal through its receptor signal regulatory protein alpha (SIRPα). Interference with the CD47-SIRPα interaction synergizes with tumor-specific monoclonal antibodies to eliminate human tumor xenografts by enhancing macrophagemediated antibody-dependent cellular phagocytosis (ADCP), but synergy between CD47 blockade and ADCP has yet to be demonstrated in immunocompetent hosts. Here, we show that CD47 blockade alone or in combination with a tumor-specific antibody fails to generate antitumor immunity against syngeneic B16F10 tumors in mice. Durable tumor immunity required programmed death-ligand 1 (PD-L1) blockade in combination with an antitumor antibody, with incorporation of CD47 antagonism substantially improving response rates. Our results highlight an underappreciated contribution of the adaptive immune system to anti-CD47 adjuvant therapy and suggest that targeting both innate and adaptive immune checkpoints can potentiate the vaccinal effect of antitumor antibody therapy.

Original languageEnglish (US)
Pages (from-to)E2646-E2654
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number19
DOIs
StatePublished - May 10 2016

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Antibodies
Neoplasms
Phagocytosis
Immunity
Ligands
Neoplasm Antibodies
Blocking Antibodies
Adaptive Immunity
Heterografts
Innate Immunity
Immune System
Proteins
Therapeutics
Monoclonal Antibodies

Keywords

  • Cancer|macrophage
  • Immunotherapy
  • Protein engineering
  • T cell

ASJC Scopus subject areas

  • General

Cite this

Durable antitumor responses to CD47 blockade require adaptive immune stimulation. / Sockolosky, Jonathan T.; Dougan, Michael; Ingram, Jessica R.; Ho, Chia Chi M; Kauke, Monique J.; Almo, Steven C.; Ploegh, Hidde L.; Garciaa, K. Christopher.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 19, 10.05.2016, p. E2646-E2654.

Research output: Contribution to journalArticle

Sockolosky, Jonathan T. ; Dougan, Michael ; Ingram, Jessica R. ; Ho, Chia Chi M ; Kauke, Monique J. ; Almo, Steven C. ; Ploegh, Hidde L. ; Garciaa, K. Christopher. / Durable antitumor responses to CD47 blockade require adaptive immune stimulation. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 19. pp. E2646-E2654.
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