[PubMed] [Google Scholar]Ross R, Sudowe S, Beisner J, Ross XL, Ludwig-Portugall I, Steitz J, Tting T, Knop J, and Reske-Kunz AB (2003)

[PubMed] [Google Scholar]Ross R, Sudowe S, Beisner J, Ross XL, Ludwig-Portugall I, Steitz J, Tting T, Knop J, and Reske-Kunz AB (2003). NP-G2C044 simultaneously limits tumor metastasis and reinvigorates anti-tumor immune responses. Graphical Abstract In brief Wang et al. report that fascin inhibitors act on intratumoral dendritic cells to block the migration and increase the antigen uptake. Together with anti-PD-1 antibody, fascin inhibitors increase the number of intratumoral proliferating and activated CD8+ T cells and the overall Arhalofenate survival of mice bearing the otherwise anti-PD-1 refractory tumors. INTRODUCTION Fascin is the main actin cross-linker in filopodia and shows no amino acid sequence homology with other actin-binding proteins (Bryan and Kane, 1978; Hashimoto et al., 2011; Li et al., 2014; Mattila and Lappalainen, 2008; Otto et al., 1979; Schoumacher et al., 2014; Tan et al., 2013; Yamashiro-Matsumura and Matsumura, 1985). Fascin regulates actin cytoskeletal reorganization during filopodial formation, lamellipodial formation, stress fiber formation, and focal adhesion turnover (Elkhatib et al., 2014; Han et al., 2016). Elevated levels of fascin have been found in many types of metastatic tumors and are correlated with clinically aggressive phenotypes, poor prognosis, and shorter survival (Tan et al., 2013). Human fascin expression is low or absent in normal adult epithelial cells but highly expressed in metastatic tumors (Grothey et al., 2000; Hashimoto et al., 2005; Snyder et al., 2011, 2014). Mouse genetic studies have shown that deletion of the fascin gene delayed tumor development, slowed the tumor growth, reduced metastatic colonization, and increased overall survival in a mouse model of pancreatic cancer (Li et al., 2014). Conversely, transgenic expression of fascin in mouse intestinal epithelium increased the tumor incidence, promoted tumor progression, and decreased the overall survival (Schoumacher et al., 2014). We previously screened chemical libraries and identified small-molecule compounds that specifically inhibit the biochemical function of fascin to bundle actin filaments (Chen et al., 2010; Han et al., 2016; Huang et al., 2015; Wang et al., 2020). X-ray crystal structural studies revealed Rabbit Polyclonal to EMR1 that the fascin inhibitor occupies one actin-binding site and induces a large conformational change of fascin to impair the actin-bundling function of fascin (Huang et al., Arhalofenate 2018; Yang et al., 2013). Cancer care has changed dramatically since the approval of the immune checkpoint inhibitors (ICIs). Yet, significant unmet medical needs remain. In indications such as melanoma and non-small-cell lung cancer (NSLCL), ICIs are having a major impact on a subset of patients, but they need to be enhanced to expand the treatment-responsive patient population. In other indications such as pancreatic cancer, new drugs (such as pioneering alternative immunomodulatory strategies) to partner with ICIs are needed for the immunotherapy concept to work at all. Cancer immunotherapy uses a patients own immune system to help fight cancer. Tumor cells suppress immune responses by activating negative regulatory pathways (also called checkpoints) that are associated with immune homeostasis or by adopting features that enable them to escape detection (Sharma and Allison, 2015). Two such checkpoints called CTLA-4 and PD-1 have garnered the most attention. The cell-surface receptor PD-1 is expressed by T cells on activation during priming or expansion and binds to one of the two ligands PD-L1 and PD-L2 (Chen and Mellman, 2017). Blocking these checkpoints elicits anti-tumor responses in mice and in cancer patients. However, up to ~85% of patients present with innate or acquired resistance to ICIs, limiting its clinical utility. Here, we discover that fascin blockade can serve as a cancer immunotherapy. Fascin inhibitor can act on dendritic cells (DCs) within the tumor microenvironment (TME). Given the current low response rates to ICIs in the clinics, fascin inhibitors might provide improvements in the clinical care of cancer patients. RESULTS NP-G2C044 increases overall survival synergistically with ICIs We started by investigating whether anti-metastasis agents, such as fascin inhibitors, could be used in combination therapy with ICIs. We explored the Arhalofenate effects on the overall survival of tumor-bearing mice of combining ICIs and a fascin inhibitor, NP-G2C044, which blocks tumor cell migration, invasion, and metastasis (Han et al., 2016; Huang et al., 2015, 2018; Wang et al., 2020). We first used the syngeneic model of the poorly immunogenic 4T1 mouse triple-negative breast tumor cells in BALB/c mice with an intact immune system. 4T1 tumor cells are considered to be refractory to ICI treatments (Charles River Laboratories syngeneic mouse models, https://www.criver.com/resources/syngeneic-model-data). 4T1 tumor cells were originally derived from a spontaneously arising mammary tumor in BALB/c mice that aggressively metastasizes, causing a uniformly lethal disease (Pulaski and Ostrand-Rosenberg, 1998). 4T1 tumor cells were implanted into the mammary gland of BALB/c.