IFITM PROTEINS REGULATE IMMUNE-RELATED CELL SURFACE MOLECULES IN CERVICAL CARCINOMA
|Interferon-induced transmembrane (IFITM) proteins form a family of plasma and endosome membrane proteins expressed by most cell types especially as a response to interferon stimulation. IFITMs are a part of innate immune response against a broad range of viruses. Besides, IFITMs also regulate adaptive immune system, especially immune cell activation and development. Deregulated expression of IFITMs has been described in most types of solid tumors as well as hematolymphoid malignancies. Using a human cervical cancer model, we have previously described that IFITMs are linked with tumor immunogenicity through regulation of major histocompatibility complex class I exposure level on tumor cell surface. Moreover, IFITM expression inversely correlates with lymph node positive cervical cancers. To further clarify the role of IFITMs in metastasis and immunity, we determined changes in surfaceome of IFITM1-deficient Siha cervical cancer cell line using differential proteomics approach. Revealed cell surface protein alterations could affect interactions between tumor and immune cells. We performed a validation analysis of preselected candidate proteins that confirmed a downregulation of CD166 and CD40 in IFITM1 and IFITM3 deficient SiHa derivatives established by CRISPR/Cas method. We further focus on functional analysis of CD166 protein (ALCAM, „activated leukocyte cell adhesion molecule“). Beyond cancer-stem cell marker function, CD166 serves as a CD6 ligand and thus intervenes in the T cell activation process. CD166 also regulates epithelial-mesenchymal transition, adhesion and metastatic spread of cancer cells. In our model, CD166 and IFITM proteins support cervicosphere formation and tumor cell migration. Interestingly, SiHa cell line sorted according to CD166 surface level exerts inversed IFITM1 expression and a transient CD166 silencing resulted in IFITM1 downregulation that confirms a reciprocalrelationship between these proteins. Despite IFITM and CD166 overexpression and pro-carcinogenic role in different cancers, these proteins possibly help tumor immunosurveillance and thus prevent cervical cancer spread. The mutual regulation of IFITMs and CD166 described here might be important for better understanding of the relationship between the innate and adaptive immunity.