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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 FcγR 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.
Pubmed ID: 30290143 RIS Download
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View all literature mentionsTHIS RESOURCE IS NO LONGER IN SERVICE. Documented on May 5,2022.Tool that predicts interactions between transcription factors and their regulated genes from binding motifs. Understanding vertebrate development requires unraveling the cis-regulatory architecture of gene regulation. PRISM provides accurate genome-wide computational predictions of transcription factor binding sites for the human and mouse genomes, and integrates the predictions with GREAT to provide functional biological context. Together, accurate computational binding site prediction and GREAT produce for each transcription factor: 1. putative binding sites, 2. putative target genes, 3. putative biological roles of the transcription factor, and 4. putative cis-regulatory elements through which the factor regulates each target in each functional role.
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View all literature mentionsThis isotype control targets Not Applicable
View all literature mentionsThis monoclonal targets IDO
View all literature mentionsThis monoclonal targets Mouse IgG2b, kappa Isotype Control
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View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis unknown targets Rabbit IgG (H+L)
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis polyclonal targets Mouse IgG (H+L)
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
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View all literature mentionsThis monoclonal targets PD-L1 (B7-H1)
View all literature mentionsThis monoclonal targets PD-L1 (B7-H1)
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View all literature mentionsThis monoclonal targets CD45
View all literature mentionsThis monoclonal targets CD45
View all literature mentionsThis monoclonal targets CD56
View all literature mentionsThis monoclonal targets CD14
View all literature mentionsThis monoclonal targets CD8
View all literature mentionsThis monoclonal targets CD274
View all literature mentionsThis monoclonal targets CD274
View all literature mentionsThis monoclonal targets CD274 (B7-H1, PD-L1)
View all literature mentionsThis monoclonal targets CD28
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View all literature mentionsCell line SK-BR-3 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsMus musculus with name B6.Cg-Pds5bTg(Wap-ERBB2)229Wzw/J from IMSR.
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Mus musculus with name NOD.Cg-Prkdcscid Il2rg
Mus musculus with name B6.129P2-Aim2Gt(CSG445)Byg/J from IMSR.
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View all literature mentionsCell line Raji is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line BT-474 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
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