TY - JOUR
T1 - IgE Activates Monocytes from Cancer Patients to Acquire a Pro-Inflammatory Phenotype.
AU - Nakamura, Mano
AU - Souri, Elmira Amiri
AU - Osborn, Gabriel
AU - Laddach, Roman
AU - Chauhan, Jitesh
AU - Stavraka, Chara
AU - Lombardi, Sara
AU - Black, Anna
AU - Khiabany, Atousa
AU - Khair, Duaa O.
AU - Figini, Mariangela
AU - Winship, Anna
AU - Ghosh, Sharmistha
AU - Montes, Ana
AU - Spicer, James F.
AU - Bax, Heather J.
AU - Josephs, Debra H.
AU - Lacy, Katie E.
AU - Tsoka, Sophia
AU - Karagiannis, Sophia N.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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 (TNFα, MCP-1, IL-10, CXCL-10, IL-1β, 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 FcεRI on monocytes stimulated the phosphorylation of intracellular protein kinases widely reported to be downstream of mast cell and basophil tetrameric FcεRI signalling. These included recently-identified FcεRI 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.
AB - 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 (TNFα, MCP-1, IL-10, CXCL-10, IL-1β, 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 FcεRI on monocytes stimulated the phosphorylation of intracellular protein kinases widely reported to be downstream of mast cell and basophil tetrameric FcεRI signalling. These included recently-identified FcεRI 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.
KW - cancer
KW - cancer immunotherapy
KW - cytotoxicity
KW - AllergoOncology
KW - cross-linking
KW - FcεRI
KW - IgE
KW - monocytes
U2 - 10.3390/cancers12113376
DO - 10.3390/cancers12113376
M3 - Article
VL - 12
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 11
ER -