Endoplasmic reticulum stress regulates tumor growth and anti-tumor immunity: a promising opportunity for cancer immunotherapy

Abstract

The endoplasmic reticulum (ER) stress is a cellular process that occurs as a consequence of several stress circumstances, such as the accumulation of unfolded proteins in the lumen of the ER or distinct insults that disturb the ER normal function. Different conditions in the tumor microenvironment (TME), including hypoxia, nutrient deprivation, and the elevated production of reactive oxygen and nitrogen species destabilize the loading and dispatching of the newly synthesized proteins, triggering ER stress in cancer cells and tumor-infiltrating leukocytes. In order to cope with TME-induced ER stress, tumor and stromal cells initiate an adaptive response process that aims to resolve ER stress and to restore cellular homeostasis, which is referred as the Unfolded Protein Responses (UPR). Paradoxically, the UPR can also induce cell death under severe and/or permanent ER stress. The UPR is started through three mediators, the activation of the inositol-requiring enzyme-1α (IRE-1α), the pancreatic ER kinase (PKR)-like ER kinase (PERK), and the activating transcription factor 6 (ATF6). In this minireview, we will discuss the pro and anti-tumorigenic role of the UPR in cancer cells. In addition, we will describe the effects of the TME-induced ER stress in the immunosuppressive activity of tumor-infiltrating myeloid cells. Also, we will review the results of emerging therapeutic interventions that target ER stress and the UPR mediators in cancer. We postulate that the inhibition of ER stress or the UPR-related elements could represent a significant approach to increase the efficacy of various forms of cancer immunotherapy.

Role of telomerase in the tumour microenvironment

“…The tumour microenvironment (TME) is the local environment where malignant cells strive and survive, and is composed of cancers cells and their surroundings such as blood vessels, extracellular matrix (ECM), infiltrating immune cells, fibroblasts, and signalling molecules . In addition, cancer stem cells (CSCs) and endoplasmic reticulum (ER) stress influence the properties of the TME to benefit tumour cell growth . The cross‐talk between the cancer cells and their environment involves numerous oncogenic transcription factors.…”

Endoplasmic Reticulum-Associated Degradation-Dependent Processing in Cross-Presentation and Its Potential for Dendritic Cell Vaccinations: A Review

“…The role of ERAD-dependent processing in CP strongly suggests that ex vivo methods, which enhance recognition of extracellular proteins as the ERAD substrate, would significantly improve the effect of DC vaccination. On the contrary, the overactivation of UPR impairs both antigen presentation and the immunoregulatory activity of DCs, and even differentiates monocytes into MDSCs or MDSC-like cells [62,63]. This indicates that the application of ERAD-dependent molecular machinery may have extensive potential to improve CP efficiency.…”

“…However, moDCs can be induced from blood monocytes in vitro using GM-CSF, and thus are not difficult to collect in high numbers in contrast to cDC1s [62]. Monocytes are also able to differentiate into myeloid-derived suppressor cells (MDSCs), or MDSC-like suppressor cells in some cases, which suppress anti-cancer immunity in both humans and mice [63]. These results indicate that further research is required to elucidate the prospects of human moDCs for DC vaccines.…”

“…TES imparts BMDCs with a mixed pro-inflammatory/immunosuppressive phenotype to promote cancer survival and outgrowth, although the precise molecular mechanisms are not clarified yet [62]. Moreover, during TES, monocytes differentiate into MDSCs, which accumulate in cancers and block protective anti-cancer T cell responses in both humans and mice [63]. All of these results indicate that the molecular machinery of ERAD-dependent processing has great potential to increase CP efficiency, and further investigation is essential to make good use of this for DC vaccines.…”

Ping-Pong—Tumor and Host in Pancreatic Cancer Progression

“…The dectin1-galectin9 axis is central in directing the differentiation of TAM to a M2like phenotype, which suffices for reprogramming CD4+ and CD8+ T-cells (749). Finally, we list some reviews helpful as starting information on PaCa-selective metabolic changes that affect immune responses in PaCa (739,(750)(751)(752)(753)(754).…”