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, 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.

Keywords: Endoplasmic reticulum stress; Myeloid-derived suppressor cells; Regulatory myeloid suppressor cells; T cells; Tumor microenvironment; Unfolded protein responses.

Fig. 1

UPR mediators have versatile roles in different cell types either in the presence of balanced or unresolved ER stress. Under physiological conditions, the balanced UPR is crucial for the development of cells with secretory functions as pancreatic β islets, hepatocytes, and B lymphocytes. Also, the maturation and the antigen-presenting capability of CD8α DCs require moderated activation of UPR that is mediated though IRE1α-XBP-1 pathway. Furthermore, the effect of the balanced UPR in the T cell development and function is emerging. An exaggerated form of UPR can be triggered by different stress factors associated with pathological conditions as infections, autoimmunity, and cancer. Tumors cells either survive or undergo ICD depending on the degree of UPR severity. Tumor-infiltrating myeloid cells (t-DC, TAM, and MDSC) are characterized by sustained and amplified UPR activity which converts them into immunosuppressive cells that promote tumor growth and invasion

Fig. 2

Myeloid cells originate from precursors in the bone marrow and transfer through blood stream until they reach tumor sites. Stress conditions in the tumor microenvironment activate UPR pathways which either retain tumor-infiltrating myeloid cells in an immature stage or switch them to tolerogenic populations that can blunt T cells. Therapeutic approaches to block UPR mediators can reprogram immature tumor-infiltrating myeloid cells into professional antigen-presenting cells rather than immunosuppressive phenotypes. As such, the inhibition of the UPR mediators could serve as a major opportunity for cancer treatments