Interferon signaling restrains renal cell carcinoma heterogeneity

Abstract

Type I interferon (IFN) is central to cancer surveillance as it mediates both direct and immune-mediated oncosuppressive effects. A recent study by Perelli et al. suggests that the ability of renal cancer cells to tolerate complex karyotypic alterations elicited by chromosomal instability (CIN), and ultimately acquire full metastatic potential, is also negatively regulated by IFN signaling.

Keywords: CGAS; CNV; cancer stem cells; cancer/immunity coevolution; immunoevasion.

Figure 1.. Oncosuppressive activity of type I IFN.

A. Upon disruption of chromosome 4p mouse renal cancer cells acquire elevated levels of chromosomal instability (CIN), which is accompanied by the acquisition of intratumoral heterogeneity. Type I interferon (IFN) signaling limits such process by promoting cell senescence and death via cancer-cell intrinsic mechanisms driven by type I IFN receptors (IFNARs). In line with this notion, loss of chromosome 16q, which encodes for several IFN receptors, is positively selected by evolutionary mechanisms, resulting in accrued cancer cell malignancy and heterogeneity. B. Type I IFN exerts potent oncosuppressive effects via direct and indirect (including immunological) mechanisms. Cancer cells evading such mechanisms, for instance upon IFNAR downregulation or via the establishment of an immunosuppressive tumor microenvironment (TME), are hence advantaged and generate rapidly progressing and heterogenous neoplasms. RCD, regulated cell death.