Predicting the Efficacy of HER2-Targeted Therapies: A Look at the Host

Figure 1

Anti-HER2 therapies and their immunostimulatory properties. The monoclonal antibodies trastuzumab and pertuzumab, in addition to inhibiting intracellular signaling downstream of HER2 activation (i.e., homo/heterodimerization and proteolytic cleavage of the HER2 extracellular domain), induce an antitumor immune response in the tumor microenvironment. Trastuzumab and pertuzumab bind to the extracellular domain of HER2 and, through their Fc portions, engage antibody-dependent cell-mediated cytotoxicity (ADCC) and phagocytosis (ADCP) in Fc receptor-positive innate immune cells (i.e., NK lymphocytes, macrophages, monocytes, and neutrophils). Immune complex and opsonized tumor fragments are recognized and taken up by dendritic cells via the Fc receptor. Dendritic cells and other antigen-presenting cells (e.g., macrophages) present tumor antigens through MHC-II molecules to CD4+ T-helper lymphocytes, which release interferon-γ (IFNγ), interleukin 2 (IL2), and IL21 to enhance the cytotoxic T cell response. Antigens presented by MHC-I molecules directly stimulate CD8+ cytotoxic T lymphocytes. CD8+ T cells can also recognize tumor antigens presented on MHC-I molecules by cancer cells themselves and initiate a cytotoxic response. Tyrosine kinase inhibitors (TKIs) (lapatinib and neratinib) block the kinase domain activity of HERs, disrupting the oncogenic signals that lead to proliferation, migration, invasion, and survival of cancer cells. In contrast to neratinib, lapatinib, in addition to blocking the TK domain of HER2 and HER1, affects the accumulation of HER2 on the surface of BC cells, leading to an increase in ADCC when combined with trastuzumab.