Abstract
The tumor-immune interface has surged to primary relevance in an effort to understand the hurdles facing immune surveillance and cancer immunotherapy. Reports over the past decades have indicated a role for the unfolded protein response (UPR) in modulating not only tumor cell fitness and drug resistance, but also local immunity, with emphasis on the phenotype and altered function of immune cells such as myeloid cells and T cells. Emerging evidence also suggests that aneuploidy correlates with local immune dysregulation. Recently, we reported that the UPR serves as a link between aneuploidy and immune cell dysregulation in a cell nonautonomous way. These new findings add considerable complexity to the organization of the tumor microenvironment (TME) and the origin of its altered function. In this review, we summarize these data and also discuss the role of aneuploidy as a negative regulator of local immunity.
Highlights
The tumor-immune interface is a variable of fundamental relevance to understand what determines tumor evolution
In 2011 we reported that cancer cells of various origin undergoing a unfolded protein response (UPR) release a diffusible factor(s) that transmits endoplasmic reticulum (ER) stress to receiver myeloid cells, macrophages and dendritic cells, triggering the secretion of pro-inflammatory/tumorigenic cytokines and the immune suppressive factor Arginase 1 (Arg1) [64, 65]
An analysis of the three branches of the UPR by PCR and Western blotting in human cancer cells treated with Rv showed that aneuploidy triggers a global UPR including the upregulation of GRP78, and an overall activation of both PKR-like ER kinase (PERK) and IRE1a branches, with phosphorylation of eukaryotic translation initiation factor 2a (eIF2a) downstream of PERK being the hallmark of PERK involvement
Summary
The tumor-immune interface is a variable of fundamental relevance to understand what determines tumor evolution. We will discuss recent data showing that aneuploidy is the source of UPR in cancer cells and this can lead to cell-nonautonomous dysregulation of immune cells, T cells and macrophages.
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