Antibody-dependent Tumor Phagocytosis Enhances PD-L1 and IDOs Expression on Macrophages, Which Mediate Trastuzumab Resistance in Her2+ Breast Cancer

Abstract

Abstract The immune response has been linked to the therapeutic effect of trastuzumab, the monoclonal antibody against Her2. However, the underlying mechanism remains unclear. Here, we reported that the infiltration of tumor-associated macrophages is associated with the reduction of CD8+ T cells and NK cells in tumors and poor response of trastuzumab-containing neo-adjuvant chemotherapy in Her2+ breast cancer patients. In vitro, the macrophages suppress proliferation and tumoricidal effect of CD8+ T cells and NK cells after phagocytosis of Her2+ tumor cells mediated by trastuzumab in a CD16 and CD32a-dependent manner. By using global expression screening, we identified the immunosuppression effect is due to the upregulation of PD-L1 and IDOs on macrophages after tumor phagocytosis. Accordingly, optimal response of 4D5, the mouse anti-human Her2 antibody as trastuzumab parental drug, require macrophage depletion or anti-PD-L and IDO inhibition in tumor-bearing mice. In consistent with results form mice, the expression of PD-L1 and IDOs on tumor-associated macrophages increase in clinical samples of patients who received trastuzumab-containing neo-adjuvant chemotherapy, but not in those of patients who received neo-adjuvant chemotherapy without trastuzumab. Collectively, our data suggest that trastuzumab and double immune checkpoint blockade exert non-redundant clinical effects on Her2+ breast cancer patients with dense tumor-associated macrophages infiltration.