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

  • Focussed Research Review
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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, the pancreatic ER kinase-like ER kinase, and the activating transcription factor 6. 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.

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Abbreviations

A-NEC:

Acute necrotizing enterocolitis

ATF4:

Activation transcription factor 4

ATF6:

Activating transcription factor 6

C/EBP:

CAAT/enhancer binding protein

cDCs:

Conventional dendritic cells

CHOP:

CAAT/enhancer binding protein (C/EBP) homologous protein

CRT:

Calreticulin

DAMPs:

Danger-associated molecular patterns

DR5:

TNF-related apoptosis-induced ligand receptor 2

EAE:

Autoimmune encephalomyelitis

eIF2α:

Eukaryotic initiation factor 2α

ER stress:

Endoplasmic reticulum stress

ERAD:

ER-associated degradation

HIF-1α:

Hypoxia-inducible factor 1 alpha

ICD:

Immunogenic cell death

IRE-1α:

Inositol-requiring enzyme-1α

Kdelr1:

KDEL receptor 1

LOX-1:

Lectin-type oxidized LDL receptor-1

M-MDSC:

Monocytic MDSC

MDSC:

Myeloid-derived suppressor cells

Nrf2:

NF-E2-related factor-2

PERK:

Pancreatic ER kinase (PKR)-like ER kinase

PKR:

Protein kinase RNA

PMN-MDSC:

Granulocytic MDSC

PRR:

Pathogen recognition receptors

RIDD:

IRE-1-dependent decay of mRNA

ROS:

Reactive oxygen species

Rpl22:

RP ribosomal protein L22

t-DC:

Tumor-infiltrating dendritic cells

TAM:

Tumor-associated macrophages

Th2:

Type 2 T helper cells

TLRs:

Toll-like receptors

TME:

Tumor microenvironment

TNBC:

Triple-negative breast cancer

TRAF2:

TNF receptor-associated factor 2

UPR:

Unfolded protein responses

VEGF-A:

Vascular endothelial growth factor A

XBP-1:

X-box binding protein-1

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Acknowledgements

This work was partially supported by the National Cancer Institute, NIH Grant No. CA18485 to Paulo C. Rodriguez, PhD.

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Authors and Affiliations

  1. Georgia Cancer Center, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd, Room CN-4125A, Augusta, GA, 30912, USA

    Eslam Mohamed & Yu Cao

  2. Department of Medicine, Georgia Cancer Center, Augusta University, 1410 Laney Walker Blvd, Room CN-4114, Augusta, GA, 30912, USA

    Paulo C. Rodriguez

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  1. Eslam Mohamed
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  2. Yu Cao
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Correspondence to Eslam Mohamed or Paulo C. Rodriguez.

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This paper is a Focussed Research Review based on a presentation given at the conference Regulatory Myeloid Suppressor Cells: From Basic Discovery to Therapeutic Application which was hosted by the Wistar Institute in Philadelphia, PA, USA, 16th–19th June, 2016. It is part of a Cancer Immunology, Immunotherapy series of Focussed Research Reviews.

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Mohamed, E., Cao, Y. & Rodriguez, P.C. Endoplasmic reticulum stress regulates tumor growth and anti-tumor immunity: a promising opportunity for cancer immunotherapy. Cancer Immunol Immunother 66, 1069–1078 (2017). https://doi.org/10.1007/s00262-017-2019-6

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