Abstract A155: Antibody-dependent cancer cell phagocytosis in macrophages induces immune escape by upregulating PD-L1 and IDO

Abstract

Therapeutic antibodies can exert anticancer effects via antibody-dependenT-cellular cytotoxicity (ADCC). Also, they may trigger antibody-dependenT-cellular phagocytosis (ADCP) in tumor-associated macrophages (TAMs), but how ADCP influences TAM functions and antitumor immunity remains unclear. Here, we demonstrated that TAMs undergone ADCP of breast cancer cells and lymphoma cells mediated by trastuzumab and rituximab, respectively, suppressed the proliferation and cytotoxicity of NK cells and tumor-specific CD8+ T-cells against tumor cells by increasing PD-L1 and IDO. In vivo, inhibition of PD-L1 and IDO dramatically increases the infiltration of NK cells and CD8+ T-cells in Her2+ breast cancers and enhances the therapeutic effects of anti-Her2 antibody in both human Her2 knockin mice and humanized mice. Clinically, trastuzumab, but not chemotherapy alone, significantly increased the expression of PD-L1 and IDO in the TAMs of Her2+ breast cancer patients receiving neoadjuvant therapy. Furthermore, PD-L1+ IDO+ TAM infiltration was associated with poor trastuzumab response and reduced NK and CD8+ T-cells in tumors. Collectively, our findings unveil an unexpected role of ADCP mediated by therapeutic monoclonal antibodies in cancer immunosuppression, and suggest that antibody plus immune checkpoint blockade provide synergic therapeutic effects in cancer patients. Citation Format: Shicheng Su, An Su. Antibody-dependent cancer cell phagocytosis in macrophages induces immune escape by upregulating PD-L1 and IDO [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A155.