Journal
CELL
Volume 175, Issue 2, Pages 442-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.09.007
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Funding
- National Key Research and Development Program of China [2016YFC1302300, 2017YFA0106300]
- National Key Basic Research Program of China (973 Project) [2015CB553702]
- Natural Science Foundation of China [81622036, 81472468, 81672614, 81720108029, 81621004, 81490750, 81672619, 81630074, 81472467]
- Guangdong Science and Technology Department [2016A030306023, 2014A030313094, 2017A030313878, 2016B030229004, 2015B050501004]
- Guangdong Science and Technology Department International Collaboration Key Project [2014A050503034, 411255676029]
- Tip-top Scientific and Technical Innovative Youth Talents of Guangdong Special Support Program [2016TQ03R553]
- Guangzhou Science Technology and Innovation Commission [201804020076, 201508020008, 201803040015]
- Guangzhou Pearl River Science and Technology Nova Program [201710010083]
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Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) critically contribute to the efficacy of anti-tumor therapeutic antibodies. We report here an unexpected finding that macrophages after ADCP inhibit NK cell-mediated ADCC and T cell-mediated cytotoxicity in breast cancers and lymphomas. Mechanistically, AIM2 is recruited to the phagosomes by Fc gamma R signaling following ADCP and activated by sensing the phagocytosed tumor DNAs through the disrupted phagosomal membrane, which subsequently upregulates PD-L1 and IDO and causes immunosuppression. Combined treatment with anti-HER2 antibody and inhibitors of PD-L1 and IDO enhances anti-tumor immunity and anti-HER2 therapeutic efficacy in mouse models. Furthermore, neoadjuvant trastuzumab therapy significantly upregulates PD-L1 and IDO in the tumor-associated macrophages (TAMs) of HER2(+) breast cancer patients, correlating with poor trastuzumab response. Collectively, our findings unveil a deleterious role of ADCP macrophages in cancer immunosuppression and suggest that therapeutic antibody plus immune checkpoint blockade may provide synergistic effects in cancer treatment.
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