Fascin in Adaptive Immune Response

Fascin is an actin-bundling protein with restricted expression in normal cells including neurons and immune cells. Aberrant fascin expression was reported in many cancer types and its expression levels in cancer cells correlate with poor prognosis. Small compounds that selectively target fascin showed promising results in numerous preclinical animal studies and phase I/II clinical trial against many solid malignancies.

We have previously demonstrated high fascin expression only in mature dendritic cells (DCs), while it was not detected in other tested immune cells such as T or B cells. Fascin is polarized in DCs at the interface with T cells and its in vitro silencing reduced antigen presentation ability of DCs. However, the effect of fascin loss on the fate of immune response following in vivo antigen challenge has not been tested. Therefore, we hypothesized that alteration of fascin activity in DCs may affect both the magnitude and quality of the adaptive immune responses following vaccination. In this study, we propose to challenge fascin knockout mice with a known T-dependent model antigen (ovalbumin) to determine if fascin loss influences the magnitude or the quality of the induced memory T cell response.

We believe that, in vivo inhibition of fascin’s activity, either through genetic knockdown or the use of fascin-specific small molecules, is a double-edged sword, as it could influence the immune response in addition to its primary objective of halting the tumor growth. Therefore, the results from our studies will not only enhance our understanding of fascin’s role in memory T cell responses but also guide future use of fascin-selective inhibitors as anti-cancer agents. Moreover, the outcome of this study could open new areas of research where fascin’s activity is inhibited to suppress responses, such as in autoimmune diseases or following transplantation. Alternatively, development of new therapeutic approaches that augment fascin expression in DCs could be leveraged to boost immunotherapeutic efficiency.