Abstract
Human FAT1 is overexpressed on the surface of most colorectal cancers (CRCs) and in particular a 25 amino acid sequence (D8) present in one of the 34 cadherin extracellular repeats carries the epitope recognized by mAb198.3, a monoclonal antibody which partially protects mice from the challenge with human CRC cell lines in xenograft mouse models. Here we present data in immune competent mice demonstrating the potential of the D8-FAT1 epitope as CRC cancer vaccine. We first demonstrated that the mouse homolog of D8-FAT1 (mD8-FAT1) is also expressed on the surface of CT26 and B16F10 murine cell lines. We then engineered bacterial outer membranes vesicles (OMVs) with mD8-FAT1 and we showed that immunization of BALB/c and C57bl6 mice with engineered OMVs elicited anti-mD8-FAT1 antibodies and partially protected mice from the challenge against CT26 and EGFRvIII-B16F10 cell lines, respectively. We also show that when combined with OMVs decorated with the EGFRvIII B cell epitope or with OMVs carrying five tumor-specific CD4+ T cells neoepitopes, mD8-FAT1 OMVs conferred robust protection against tumor challenge in C57bl6 and BALB/c mice, respectively. Considering that FAT1 is overexpressed in both KRAS+ and KRAS− CRCs, these data support the development of anti-CRC cancer vaccines in which the D8-FAT1 epitope is used in combination with other CRC-specific antigens, including mutation-derived neoepitopes.
Highlights
Human FAT atypical cadherin 1 (FAT1) is a type 1 transmembrane protein carrying 34 cadherin repeats, five EGF-like repeats, a laminin A–G domain in the extracellular region and a cytoplasmic tail [1]
FAT1 is over-expressed in most human colorectal cancers (CRCs) and the 25 amino acid hD8-FAT1 domain recognized by mAb198.3 is exposed on cancer cells and not on healthy human tissues
Murine FAT1 shares 88% identity to hFAT1 and in particular 21 out of the 25 amino acids of hD8-FAT1 are conserved in murine D8-FAT1 (Figure 1A)
Summary
Human FAT atypical cadherin 1 (FAT1) is a type 1 transmembrane protein carrying 34 cadherin repeats, five EGF-like repeats, a laminin A–G domain in the extracellular region and a cytoplasmic tail [1]. The protein undergoes a proteolytic cleavage by Furin and is predicted to be further cleaved by γ secretase so that its intracellular domain (ICD) can translocate into the nucleus and directly activate cell signaling. FAT1 ICD interacts with Ena/VAPS and Scribble, promotes actin-mediated cell migration and inhibits YAP1-mediated cell proliferation [2]. FAT1 ICD interacts with β-catenin and prevents its translocation to the nucleus [3]. FAT1 up-regulation is an unfavorable prognostic factor for precursor B-cell acute lymphoblastic leukemia patients [4] and recent studies in melanoma and pancreatic cancer have demonstrated that FAT1 undergoes an aberrant processing and an altered localization compared to normal cells [6]
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