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CD47 blockade augmentation of trastuzumab antitumor efficacy dependent on antibody-dependent cellular phagocytosis
Li-Chung Tsao, … , Herbert Kim Lyerly, Zachary C. Hartman
Li-Chung Tsao, … , Herbert Kim Lyerly, Zachary C. Hartman
Published November 5, 2019
Citation Information: JCI Insight. 2019;4(24):e131882. https://doi.org/10.1172/jci.insight.131882.
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Research Article Immunology Oncology

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

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Abstract

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.

Authors

Li-Chung Tsao, Erika J. Crosby, Timothy N. Trotter, Pankaj Agarwal, Bin-Jin Hwang, Chaitanya Acharya, Casey W. Shuptrine, Tao Wang, Junping Wei, Xiao Yang, Gangjun Lei, Cong-Xiao Liu, Christopher A. Rabiola, Lewis A. Chodosh, William J. Muller, Herbert Kim Lyerly, Zachary C. Hartman

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Figure 6

Single-cell transcriptome analysis of immune clusters within HER2+ breast cancer after trastuzumab with CD47 blockade therapy.

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Single-cell transcriptome analysis of immune clusters within HER2+ breas...
HER2+ tumors from HER2Δ16-transgenic animals were isolated for single-cell RNA sequencing using the 10× Genomics platform. Data from all tumors were pooled for clustering and gene expression analysis. (A) tSNE plots showing distinct clusters of immune cells in tumors from 4 treatment groups: control IgG, αCD47, 4D5-IgG2A, or combination. (B and C) Heatmap of relevant gene markers confirmed the various immune cell clusters in control tumors (B) and the expansion of macrophage clusters in the combination therapy–treated tumors (C). Macrophages that contained tumor-specific transcripts (e.g., hERBB2, Epcam, Krt8) were categorized as tumor-phagocytic macrophages (Phag MΦ, predominantly found in the combination treatment group).

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