IgE Activates Monocytes from Cancer Patients to Acquire a Pro-Inflammatory Phenotype.
IgE contributes to host-protective functions in parasitic and bacterial infections, often by monocyte and macrophage recruitment. We previously reported that monocytes contribute to tumour antigen-specific IgE-mediated tumour growth restriction in rodent models. Here, we investigate the impact of IgE stimulation on monocyte response, cellular signalling, secretory and tumour killing functions. IgE cross-linking on human monocytes with polyclonal antibodies to mimic formation of immune complexes induced upregulation of co-stimulatory (CD40, CD80, CD86), and reduced expression of regulatory (CD163, CD206, MerTK) monocyte markers. Cross-linking and tumour antigen-specific IgE antibody-dependent cellular cytotoxicity (ADCC) of cancer cells by cancer patient-derived monocytes triggered release of pro-inflammatory mediators (TNFalpha, MCP-1, IL-10, CXCL-10, IL-1beta, IL-6, IL-23). High intratumoural gene expression of these mediators was associated with favourable five-year overall survival in ovarian cancer. IgE cross-linking of trimeric FcepsilonRI on monocytes stimulated the phosphorylation of intracellular protein kinases widely reported to be downstream of mast cell and basophil tetrameric FcepsilonRI signalling. These included recently-identified FcepsilonRI pathway kinases Fgr, STAT5, Yes and Lck, which we now associate with monocytes. Overall, anti-tumour IgE can potentiate pro-inflammatory signals, and prime tumour cell killing by human monocytes. These findings will inform the development of IgE monoclonal antibody therapies for cancer.
|Authors:||Nakamura M, Souri EA, Osborn G, Laddach R, Chauhan J, Stavraka C, Lombardi S, Black A, Khiabany A, Khair DO, Figini M, Winship A, Ghosh S, Montes A, Spicer JF, Bax HJ, Josephs DH, Lacy KE, Tsoka S, Karagiannis SN,|
|Journal:||Cancers (Basel); 2020 Nov 15 ; 12 (11) . doi:10.3390/cancers12113376|
|PubMed:||PMID: 33203088 (Go to PubMed)|