P36 Investigating the role of the IgE–FcεRI axis in human cutaneous squamous cell carcinoma

Abstract Introduction and aims The IgE–FcεRI axis is primarily studied in the context of helminth infection and allergy. Here, we focus on IgE–FcεRI in skin cancer immune surveillance. We have previously shown in mouse models of cutaneous squamous cell carcinoma (cSCC) that autoreactive IgE is induced de novo and protects against cancer development via FceRI. FcεRI-expressing cells have also been reported in human solid cancers, with Fcer1a gene expression generally correlating with better disease outcomes. In mice and humans alike, mast cells and basophils express a tetrameric FcεRI (αβγ2); however, in humans FceRI is also expressed as a trimer (αγ2) on numerous myeloid cells. Knowledge of the trimeric receptor remains limited. Here, we investigate the expression-pattern of FcεRI in human cSCC and its function in tumour immunity. Methods We have used high-parameter spectral-unmixing flow cytometry and microscopy of human cSCC. To understand the in situ function of trimeric FcεRI+ cells, a humanized mouse model capable of switching to human IgE and expressing human FceRI was used. Results We report that in patients with cSCC, IgE–FcεRI+ cells decreased in blood compared with healthy controls. However, an average of 10% of tumour-infiltrating leucocytes (TILs) expressed FceRI and carried IgE, with this reaching 50% in some patients. TILs with the highest expression of FceRI included cDC2s, pDCs and a subset of CD14+MHCII+ cells; most notably, FceRI+ cDC1s and pDC increased in cSCC tissue. In humanized mice, we show that FcεRI is expressed in a human-like pattern and that administration of tumour-specific IgE reduced tumour growth in a transplantable tumour model. We are now investigating the mechanism whereby the IgE–FcεRI axis affects the tumour microenvironment and promotes antitumour immunity. Conclusions IgE–FcεRI signalling inhibits tumour growth. Understanding how this occurs will be relevant to cSCC and, more broadly, to other solid cancers, potentially unveiling novel targets for cancer immunotherapy.