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CD47 blockade augmentation of trastuzumab antitumor efficacy dependent on antibody-dependent cellular phagocytosis.

Publication ,  Journal Article
Tsao, L-C; Crosby, EJ; Trotter, TN; Agarwal, P; Hwang, B-J; Acharya, C; Shuptrine, CW; Wang, T; Wei, J; Yang, X; Lei, G; Liu, C-X; Muller, WJ ...
Published in: JCI Insight
December 19, 2019

The HER2-specific monoclonal antibody (mAb), trastuzumab, has been the mainstay of therapy for HER2+ breast cancer (BC) for approximately 20 years. However, its therapeutic mechanism of action (MOA) remains unclear, with antitumor responses to trastuzumab remaining heterogeneous and metastatic HER2+ BC remaining incurable. Consequently, understanding its MOA could enable rational strategies to enhance its efficacy. Using both murine and human versions of trastuzumab, we found its antitumor activity dependent on Fcγ receptor stimulation of tumor-associated macrophages (TAMs) and antibody-dependent cellular phagocytosis (ADCP), but not cellular cytotoxicity (ADCC). Trastuzumab also stimulated TAM activation and expansion, but did not require adaptive immunity, natural killer cells, and/or neutrophils. Moreover, inhibition of the innate immune ADCP checkpoint, CD47, significantly enhanced trastuzumab-mediated ADCP and TAM expansion and activation, resulting in the emergence of a unique hyperphagocytic macrophage population, improved antitumor responses, and prolonged survival. In addition, we found that tumor-associated CD47 expression was inversely associated with survival in HER2+ BC patients and that human HER2+ BC xenografts treated with trastuzumab plus CD47 inhibition underwent complete tumor regression. Collectively, our study identifies trastuzumab-mediated ADCP as an important antitumor MOA that may be clinically enabled by CD47 blockade to augment therapeutic efficacy.

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Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

December 19, 2019

Volume

4

Issue

24

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Trastuzumab
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Prognosis
  • Phagocytosis
  • Mice
  • Macrophages
  • Immunity, Innate
  • Humans
 

Citation

APA
Chicago
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Tsao, L.-C., Crosby, E. J., Trotter, T. N., Agarwal, P., Hwang, B.-J., Acharya, C., … Hartman, Z. C. (2019). CD47 blockade augmentation of trastuzumab antitumor efficacy dependent on antibody-dependent cellular phagocytosis. JCI Insight, 4(24). https://doi.org/10.1172/jci.insight.131882
Tsao, Li-Chung, Erika J. Crosby, Timothy N. Trotter, Pankaj Agarwal, Bin-Jin Hwang, Chaitanya Acharya, Casey W. Shuptrine, et al. “CD47 blockade augmentation of trastuzumab antitumor efficacy dependent on antibody-dependent cellular phagocytosis.JCI Insight 4, no. 24 (December 19, 2019). https://doi.org/10.1172/jci.insight.131882.
Tsao L-C, Crosby EJ, Trotter TN, Agarwal P, Hwang B-J, Acharya C, et al. CD47 blockade augmentation of trastuzumab antitumor efficacy dependent on antibody-dependent cellular phagocytosis. JCI Insight. 2019 Dec 19;4(24).
Tsao, Li-Chung, et al. “CD47 blockade augmentation of trastuzumab antitumor efficacy dependent on antibody-dependent cellular phagocytosis.JCI Insight, vol. 4, no. 24, Dec. 2019. Pubmed, doi:10.1172/jci.insight.131882.
Tsao L-C, Crosby EJ, Trotter TN, Agarwal P, Hwang B-J, Acharya C, Shuptrine CW, Wang T, Wei J, Yang X, Lei G, Liu C-X, Rabiola CA, Chodosh LA, Muller WJ, Lyerly HK, Hartman ZC. CD47 blockade augmentation of trastuzumab antitumor efficacy dependent on antibody-dependent cellular phagocytosis. JCI Insight. 2019 Dec 19;4(24).

Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

December 19, 2019

Volume

4

Issue

24

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Trastuzumab
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Prognosis
  • Phagocytosis
  • Mice
  • Macrophages
  • Immunity, Innate
  • Humans