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.
Highlights
20% of breast cancer (BC) overexpresses human ERBB2 (HER2), recognized as an oncogenic driver of an aggressive cancer phenotype with a poor prognosis [1, 2]
Trastuzumab was based on a HER2-specific mouse IgG1 monoclonal antibody (mAb) (4D5-IgG1, low A/I ratio), which was subsequently humanized to a human IgG1 isotype that allows for superior activation of Fc receptors [27]
Tumor-bearing mice were treated weekly with 4D5-IgG2A or clinical-grade trastuzumab to determine if they could suppress tumor growth in an immunocompetent context. We found that both 4D5-IgG2A and trastuzumab significantly suppressed HER2+ BC growth, demonstrating that murine IgG2A was capable of significant antitumor activity (Figure 1B)
Summary
20% of breast cancer (BC) overexpresses HER2, recognized as an oncogenic driver of an aggressive cancer phenotype with a poor prognosis [1, 2]. Monoclonal antibodies (mAbs) targeting HER2 were developed in the 1980s to inhibit HER2 oncogenic signaling, leading to the clinical development and regulatory approval of trastuzumab in 1998 for metastatic HER2-overexpressing BC, followed by clinical trials of trastuzumab use in the adjuvant setting. Additional HER2-targeting mAbs have been generated to improve outcomes [3, 4]. Mechanistic studies of the antitumor mechanism(s) of action (MOA) of trastuzumab and its resistance remain critical, to improve outcomes in patients with HER2+ BC, and to gain insight into mechanisms that would extend mAb therapies to other types of cancers. While suppression of HER2 signaling was a primary focus of early mechanistic studies, subsequent studies focused on the role of immunity in mediating the antitumor effects of trastuzumab [7].
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