Opinion
Reshaping the Immune Tumor Microenvironment Through IRE1 Signaling

https://doi.org/10.1016/j.molmed.2018.05.005Get rights and content

Highlights

ER stress and the UPR strongly affect tumor progression in vivo and in vitro.

The UPR is a major regulator of inflammation, cell death, angiogenesis, and metabolism. In addition, it can affect cancer cell immune recognition through processes that are yet not fully understood.

The IRE1 branch of the UPR is so far the best-documented in its ability to control cell death or survival in tumors.

An increase in IRE1 signaling has been associated with an increase in mRNA expression for key antitumor T cell markers in tumors from colorectal, glioblastoma, and cancer melanoma patients.

The ability of a tumor cell to cope with environmental and intracellular stress depends on its capacity to activate appropriate adaptive pathways. As such, the endoplasmic reticulum (ER) adjusts the adaptive capacity of tumor cells by engaging the unfolded protein response (UPR). The UPR maintains the functionality of the secretory pathway, thereby allowing tumor cells to shape their microenvironment, thus likely determining the nature of the tumor immune response. Consequently, this makes the UPR very relevant in the context of cancer therapeutics. We focus here on inositol-requiring enzyme 1α (IRE1) and compile novel molecular mechanisms demonstrating that tumoral UPR controls the tumor microenvironment (TME) and the immune response, therefore opening potential novel therapeutic avenues.

Section snippets

The UPR: Controlling the Brake of Cancer

The ability of cancer cells to respond to extrinsic and intrinsic stress depends on their capacity to successfully activate appropriate adaptive pathways 1, 2. In the course of carcinogenesis, intrinsic (e.g., oncogene-driven protein synthesis, reactive oxygen species) or extrinsic (e.g., hypoxia, nutrient shortage, chemotherapy) challenges impinge on cellular protein homeostasis (proteostasis; see Glossary) [3]. In the endoplasmic reticulum (ER), an imbalance in proteostasis leads to a

The Dual Role of the IRE1 Signaling in Cancer Cell Fate: Life or Death

The UPR can affect tumor cell biology either as a barrier to tumor development or by promoting established tumors (Figure 1). The IRE1 branch of the UPR has been so far the best-documented in its ability to control cell death or survival in tumors 9, 10. IRE1 signals are predominantly mediated by its RNase activity through either the non-conventional splicing of X-box binding protein 1 (sXBP1) mRNA or regulated IRE1-dependent decay of RNA (RIDD). IRE1 adaptive signals are mainly mediated by the

IRE1 Signaling Host Immune Cells

In vivo, tumor progression or regression not only depends on activation of the UPR in tumor cells but can also be controlled by UPR induction in stromal cells, including immune cells 2, 15. Tumor-associated dendritic cells (DCs) isolated from mice and human ovarian tumors exhibit robust sXBP1 activation compared to DCs from naive hosts. This turns out to be immunosuppressive because it promotes tumor progression and metastasis by impairing T cell activation [15]. Moreover, XBP1 depletion leads

When Tumor Cells Use IRE1 Signals To Communicate with the Immune System

Modulation of ER stress in immune cells is not the only way for the UPR to regulate the immune response. The induction of the different arms of the UPR in tumor cells can result in crosstalk between the tumor and the immune system. The UPR-dependent regulation of damage-associated molecular patterns (DAMPs), cytokines (Box 2), and transmissible ER stress (TERS, Box 3), among other signals, can result in immunosurveillance or immune system evasion (Figure 1). However, the notion that the UPR can

Nutritional Stress, IRE1 Signaling, and the Immune Response: Deeper into the Rabbit Hole

It has been shown that a decrease in calorie or food intake can induce autophagy-dependent anticancer immunosurveillance [32]. Unfortunately, the use of dietary restriction (DR) to reduce tumor growth can be very hard on cancer patients owing to the risk of cachexia and DR-related weight loss. For this reason, effort is being put into the development of different ways to mimic the benefits of DR on tumor growth, but without impacting on calorie or food intake. Previous studies have shown that

Concluding Remarks

The TME plays an important role in tumor development because it conditions drug resistance and cell survival. Chemotherapy, poor vascularization, oxygen and nutrient availability can induce stress pathways, including the UPR, that counteract these stressors at the same time impacting on TME. The UPR regulates the crosstalk between tumor cells and the immune system, potentially opening a new area of research (see Outstanding Questions and Box 4). IRE1 can either play pro- or antitumoral roles

Acknowledgments

Our work is supported by grants from the Fondation ARC pour la Recherche sur le Cancer (ARC), the Agence Nationale de la Recherche (ANR; LABEX SIGNALIFE ANR-11-LABX-0028-01), and research funding from the Canceropôle Provence-Alpes–Côte d’Azur (PACA) to J.E.R., and from the Institut National du Cancer (INCA; PLBIO2017), EU H2020 Marie Skłodowska-Curie Action (MSCA) ITN-675448 (TRAINERS), and MSCARISE-734749 (INSPIRED) to E.C.

Glossary

Angiogenesis
the formation of new blood vessels that fuel cancer cells with oxygen and nutrients.
Autophagy
an intracellular degradation process that takes place via the delivery of cytoplasmic entities to the lysosomes, where macromolecules are lysed and their components recycled.
Damage-associated molecular patterns (DAMPs)
intracellular molecules that function as ‘eat me' signals for the immune system when exposed by or released from the cell; these promote and amplify the immune response.

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      In some cases, however, the expected apoptosis outcome may not occur, such as chondrocytes experiencing dedifferentiation as an adaption response to chronic ER stress instead of cell death [12]. ER stress has been shown to have a role in several cancers, whether being capable of acting against it or promoting carcinogenesis through promoting anti-apoptosis, regulating the tumor microenvironment or helping tumor cells evade the immune system [24,25]. Several studies have shown that chemotherapeutic drugs and other compounds with anti-tumor potential promote ER stress-mediating apoptosis in tumor cells [26–28].

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      Thus, through coordination of these two (parallel) signaling modules, the PERK arm of the UPR strives to help increase the survival of ER stressed cells by facilitating ER's adaptation to stress, especially oxidative stress (Dadey et al., 2018; Karali et al., 2014; Verfaillie et al., 2012; Walter et al., 2015; Zhang et al., 2013). In comparison to PERK, that operates primarily through phosphorylation of its substrates, IRE1 arm of the UPR orchestrates a relatively more complex set of biological processes (Fig. 2) (Jwa and Chang, 2012; Reverendo et al., 2019; Rubio-Patiño et al., 2018; Sundaram et al., 2018). On one hand, activated IRE1 functions as an endoribonuclease or RNase to splice X-Box binding protein 1 (XBP1) mRNA (or XBP1u), and cause the emergence of a fully functional form of it, i.e., spliced XBP1 (XBP1s) (Hassler et al., 2015; Lee et al., 2002; Mimura et al., 2012; Yanagitani et al., 2011; Yoshida et al., 2006).

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