Newly synthesised secretory and transmembrane proteins are processed by the endoplasmic reticulum (ER). A disruption in this functionality of the ER could cause a state called “ER stress”, which is a hallmark feature of secretory cells and many diseases namely diabetes, neurodegeneration and cancer.
A study lead by Cubillos-Ruiz et al, from Weill Cornell Medical College, New York have proposed a mechanism by which XBP1, a stress sensor of ER can control anti-tumor immunity by disrobing the dentritic cell (DC) homeostasis. Their work was published in Cell, May 2015.
To deal with the protein-folding stress often called the unfolded protein response (UPR), an integrated signal transduction pathway is triggered, and three distinct sensors on the ER membrane are stimulated: IRE1a, ATF6 and PERK. IRE1a, a kinase and being the most conserved arm of the UPR oligomerizes, autophosphorylates, and uses its endoribonuclease activity to excise a 26-nucleotide fragment from the unspliced Xbp1 mRNA and gives rise to functional XBP-1. It confers drug resistance in cancer cells by preventing drug-induced cell-cycle arrest, mitochondrial permeability and apoptosis.
During cancer progression, XBP-1 plays a functional role in promoting aberrant lipid accumulation by dysfunctional T cell-DC’s (tDC) and lipid peroxidation (adduct formation, eg 4-HNE formation) products further sustain ER stress contributing to immunosuppression in the tumor microenvironment. This study proposed a clear-cut explanation as to how XBP-1 activation contributes to malignant progression by inhibiting the development of protective anti-tumor immunity via manipulation of normal DC function, i.e. the collapse of tDC’s homeostasis inhibits its capacity to locally support T cell-mediated cytotoxicity deeply enhancing cancer progression. Another important finding in the study was that, this mechanism contributes to persistent, refractory, or recurrent cancer following treatment with surgery and first-line chemotherapy in patients with ovarian cancer (OvCa).
This discovery favoured the development of nanotechnology-based therapeutic system wherein DC-specific deletion of XBP1 could extend host survival by converting immunosuppressive tDCs into activators of type 1 immunity in OvCa-infiltrating T cells. Another hallmark of the study was, they found that therapeutic silencing of XBP1 in tDCs using siRNA-encapsulating nanocarriers reversed their immunosuppressive phenotype and prolonged host survival by inducing protective anti-tumor immune responses.
Cubillos-Ruiz and the team aim at targeting IRE1a/XBP1 signalling in cancer-bearing hosts with small molecule IRE1a inhibitors. These inhibitors could induce two parallel, mutually reinforcing anti-tumor mechanisms: the direct inhibition of cancer cell survival and the simultaneous induction of protective anti-tumor immunity. They will conduct future studies with the ray of hope to design an immunotherapeutic for OvCa and other recurring cancers.