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CD47 blockade augmentation of trastuzumab antitumor efficacy dependent on antibody-dependent cellular phagocytosis
Li-Chung Tsao1, Erika J Crosby1, Timothy N Trotter1
1Department of Surgery, Duke University, Durham, North Carolina, USA.
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.
Insights
Trastuzumab’s anti-cancer effect in HER2+ breast cancer relies on macrophage phagocytosis, not cell killing. Blocking CD47 enhances this, improving tumor response and survival.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Trastuzumab is a key therapy for HER2+ breast cancer, but its mechanism of action is not fully understood.
- Tumor responses to trastuzumab are variable, and metastatic disease remains incurable.
- Clarifying trastuzumab's mechanism could lead to improved treatment strategies.
Purpose of the Study:
- To elucidate the mechanism of action of trastuzumab in HER2+ breast cancer.
- To investigate the role of innate immunity, specifically macrophages, in trastuzumab's efficacy.
- To explore combination therapy with CD47 inhibition to enhance trastuzumab treatment.
Main Methods:
- Utilized murine and human trastuzumab (monoclonal antibody).
- Assessed antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC).
- Investigated the role of tumor-associated macrophages (TAMs) and CD47 blockade.
Main Results:
- Trastuzumab's antitumor activity depends on Fcγ receptor stimulation of TAMs and ADCP, not ADCC.
- Trastuzumab promotes TAM activation and expansion, independent of adaptive immunity.
- CD47 inhibition significantly boosted trastuzumab-mediated ADCP, TAM activity, and survival.
- CD47 expression inversely correlated with survival in HER2+ breast cancer patients.
- Combination therapy led to complete tumor regression in xenografts.
Conclusions:
- Trastuzumab's primary antitumor mechanism involves ADCP mediated by macrophages.
- CD47 blockade is a promising strategy to enhance trastuzumab efficacy in HER2+ breast cancer.
- Targeting the innate immune checkpoint CD47 can overcome resistance and improve outcomes.
