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Review
. 2017 Jan 17:5:5.
doi: 10.1186/s40425-016-0203-4. eCollection 2017.

Unfolding anti-tumor immunity: ER stress responses sculpt tolerogenic myeloid cells in cancer

Juan R Cubillos-Ruiz  1 , Eslam Mohamed  2 , Paulo C Rodriguez  3
Affiliations
Review

Unfolding anti-tumor immunity: ER stress responses sculpt tolerogenic myeloid cells in cancer

Juan R Cubillos-Ruiz et al. J Immunother Cancer. .

Abstract

Established tumors build a stressful and hostile microenvironment that blocks the development of protective innate and adaptive immune responses. Different subsets of immunoregulatory myeloid populations, including dendritic cells, myeloid-derived suppressor cells (MDSCs) and macrophages, accumulate in the stressed tumor milieu and represent a major impediment to the success of various forms of cancer immunotherapy. Specific conditions and factors within tumor masses, including hypoxia, nutrient starvation, low pH, and increased levels of free radicals, provoke a state of "endoplasmic reticulum (ER) stress" in both malignant cells and infiltrating myeloid cells. In order to cope with ER stress, cancer cells and tumor-associated myeloid cells activate an integrated signaling pathway known as the Unfolded Protein Response (UPR), which promotes cell survival and adaptation under adverse environmental conditions. However, the UPR can also induce cell death under unresolved levels of ER stress. Three branches of the UPR have been described, including the activation of the inositol-requiring enzyme 1 (IRE1), the pancreatic ER kinase (PKR)-like ER kinase (PERK), and the activating transcription factor 6 (ATF6). In this minireview, we briefly discuss the role of ER stress and specific UPR mediators in tumor development, growth and metastasis. In addition, we describe how sustained ER stress responses operate as key mediators of chronic inflammation and immune suppression within tumors. Finally, we discuss multiple pharmacological approaches that overcome the immunosuppressive effect of the UPR in tumors, and that could potentially enhance the efficacy of cancer immunotherapies by reprogramming the function of tumor-infiltrating myeloid cells.

Keywords: CHOP; ER stress; IRE1; Immunotherapy; Myeloid cells; PERK; Tumor immunology; Unfolded Protein Responses; XBP1.

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Figures

Fig. 1
Fig. 1
Hostile conditions in the tumor microenvironment such as hypoxia, nutrient deprivation and ROS can provoke ER stress and trigger the UPR in various tumor-resident cell types. Intrinsic ER stress responses in cancer cells ensure their survival under hypoxic conditions, increase expression of pro-angiogenic factors, promote metastasis and inhibit the presentation of their own antigens. Myeloid-intrinsic ER stress responses mediate reprogramming towards immunosuppressive and tolerogenic phenotypes. Induction of ER stress in myeloid cells may occur via transmissible factors released by ER-stressed cancer cells in the same milieu. Intracellular generation and accumulation of lipid peroxidation byproducts can further elicit intrinsic ER stress responses in myeloid cells. ER stress sensors therefore emerge as attractive targets for developing new immunotherapeutic approaches that may synergize with standard cancer treatments
Fig. 2
Fig. 2
The severity of ER stress and the levels of ROS in cancer cells can determine the outcome of immune responses within the tumor milieu. Intense ER stress responses induced by chemo- or radiotherapy increase ROS in cancer cells to levels that can promote immunogenic cell death (ICD), thus enhancing anti-tumor immunity. Moderate but sustained ER stress responses in cancer cells support tolerogenic and immunosuppressive functions in tumor-infiltrating myeloid cells, a process that cripples anti-cancer immunity
Fig. 3
Fig. 3
IRE1ɑ-XBP1 is one of the arms of UPR that polarizes tumor-infiltrating myeloid cells into highly immunosuppressive populations. Over activation of IRE1ɑ-XBP1 pathway by the byproduct adduct 4-hydroxy-trans-2-nonenal (4-HNE) in the tumor microenvironment (TME) shifts tumor-infiltrating dendritic cells towards a tolerogenic phenotype that promotes cancer cell growth. IRE1ɑ-XBP1 activation upregulates lectin-type oxidized LDL receptor-1 (LOX-1) that converts high density anti-tumor neutrophils to low density immunosuppressive polymorphonuclear myeloid cells (PMN-MDSCs). IL-4 and IL-6 signals synergize with IRE1ɑ-XBP1 to enhance the ability of tumor-associated macrophages to secret Cathepsin proteases, which facilitate cancer cell invasion and metastasis
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