The role of keratins in modulating carcinogenesis via communication with cells of the immune system

Abstract

Keratins are intermediate filament proteins expressed by epithelial cells and provide mechanical support for diverse epithelia. In our recent study (Sequeira et al., Nat Comm 9(1):3437), we analysed the role of keratin 76 (Krt76) in inflammation and cancer. Krt76 is expressed throughout embryonic development in the differentiated epithelial layers of a subset of stratified epithelia including tongue, palate and stomach. It is significantly downregulated in human oral squamous cell carcinoma (OSCC), correlating strongly with poor prognosis. We have shown that Krt76^-/- mice exhibit systemic inflammation with increased levels of circulating B cells, regulatory T cells and effector T cells. When mice are given a chemical carcinogen in the drinking water, tongue and gastric cancer formation is accelerated in Krt76^-/- mutant mice. Our data suggest that the increased tumour susceptibility of Krt76^-/- mice is in part due to the enhanced accumulation of regulatory T cells in the tumour microenvironment. Our results support the notion that keratins, in addition to their function as cytoskeletal components, regulate immunity and affect tumour susceptibility of epithelial cells.

Keywords: Krt76; anti-tumour; cancer; immunoregulation; keratin; regulatory T cells.

Figure 1. FIGURE 1: Summary schema of the balance between regulatory T cells (Treg) and effector T cells (Teff).

Increased numbers of Tregs and their increased suppressive function in Krt76^−/− mice leads to a decreased antitumour immune response.