Role of FHOD1 in tumor cells and tumor immune microenvironment

Abstract

FHOD 1 (Formin homology 2 domain containing protein 1) is a member of Diaphanous-related formins (DRFs) which contains a GTP-binding domain (GBD), formin homology (FH) 1 and FH 2 domains, a coiled-coil, and a diaphanous-like autoregulatory domain. Studies have shown that FHOD1 can not only regulate intracellular signals in tumor cells but also regulate various components of the tumor microenvironment (TME), such as T cells, B cells, cancer-associated fibroblasts (CAFs), some cytokines. Aberrant expression and dysfunction of the FHOD1 protein play a key role in tumor immunosuppression. Specifically, FHOD1 can impair function of chemokine receptors that are supposed to direct immune cells to localize to the tumor site accurately. As a result of this impairment, immune cells cannot migrate efficiently into TME, thereby impairing their ability to attack tumor cells. In addition, FHOD1 activated signaling pathways within the immune cells abnormally, resulting in their inability to recognize and destroy tumor cells effectively. Therefore, FHOD1 ultimately leads to a state of immunosuppression in TME, providing favorable conditions for the growth and spread of tumor cells. Altogether this review provides an in-depth understanding of the role of FHOD1 in tumor immunosuppression.

Keywords: FHOD1; PD-1; PDL1; epithelial-mesenchymal transition; tumor immune microenvironment.

Figure 1

FHOD1 modulates key signaling pathways involved in PDL 1 expression, and downstream signals of these pathways include ZEB and Snail, which are transcription factors of EMT that regulate PDL 1 expression.

Figure 2

In tumor cells, FHOD1 uses the PD-1/PDL1 pathway to evade immune surveillance mainly by inhibiting t-cell responses in the TME.

Figure 3

The covalent attachment of activated C3 d to antigen targets the complex to follicular dendritic cells. CD21 stimulates B cells to participate in the regulation of antibody production through BCR signaling mediated by immune complexes (C3d-Ab-Ag) (118). When CD21 is stimulated, the mechanical force generated by Rac1 attracts FHOD1 to the vicinity of CD21, thereby facilitating promoting the development and progression of colorectal cancer.