Endoplasmic Reticulum Stress Pathway, the Unfolded Protein Response, Modulates Immune Function in the Tumor Microenvironment to Impact Tumor Progression and Therapeutic Response

Ramirez, Manuel U.; Hernandez, Salvador R.; Soto-Pantoja, David R.; Cook, Katherine L.

doi:10.3390/ijms21010169

Cited by 39 publications

(28 citation statements)

References 177 publications

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“…The anticancer effects of the apoptotic cyclic peptide BC71 have been attributed to its ability to inhibit mGRP78 ( 23 ). Besides, GRP78 has been shown to affect tumor progression and therapeutic response by modulating the functions of immune cells found in the tumor microenvironment ( 24 ).…”

Section: Introductionmentioning

confidence: 99%

Tumor-Secreted GRP78 Promotes the Establishment of a Pre-metastatic Niche in the Liver Microenvironment

Zheng

et al. 2020

Front. Immunol.

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The liver is an immunologically tolerant organ and a common site of distant metastasis for various cancers. The expression levels of glucose-regulated protein 78 (GRP78) have been associated with tumor malignancy. Secretory GRP78 (sGRP78) released from tumor cells contributes to the establishment of an immunosuppressive tumor microenvironment by regulating cytokine production in macrophages and dendritic cells (DCs). However, the role of sGRP78 on tumor cell colonization and metastasis in the liver remains unclear. Herein, we found that GRP78 was expressed at higher levels in the liver compared to other tissues and organs. We performed intravital imaging using a sGRP78-overexpressing breast cancer cell line (E0771) and found that sGRP78 interacted with dendritic cells (DCs) and F4/80 + macrophages in the liver. Importantly, sGRP78 overexpression inhibited DC activation and induced M2-like polarization in F4/80 + macrophages. Moreover, sGRP78 overexpression enhanced TGF-β production in the liver. In conclusion, sGRP78 promotes tumor cell colonization in the liver by remodeling the tumor microenvironment and promoting immune tolerance. The ability of sGRP78-targeting strategies to prevent or treat liver metastasis should be further examined.

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Section: Introductionmentioning

confidence: 99%

Tumor-Secreted GRP78 Promotes the Establishment of a Pre-metastatic Niche in the Liver Microenvironment

Zheng

et al. 2020

Front. Immunol.

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“…The ER is an active intracellular organelle with different functions like protein folding and maturation within the eukaryotic cell, essential for cellular homeostasis, proteostasis, cellular development, and stress responsiveness ( 50 ). Aberrations in protein folding may result in an imbalance leading to the accumulation of misfolded proteins in the ER, which is known as ER stress.…”

Section: Understanding Er Stress-induced Uprmentioning

confidence: 99%

A Concise Review on the Role of Endoplasmic Reticulum Stress in the Development of Autoimmunity in Vitiligo Pathogenesis

et al. 2021

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Vitiligo is characterized by circumscribed depigmented macules in the skin resulting due to the autoimmune destruction of melanocytes from the epidermis. Both humoral as well as cell-mediated autoimmune responses are involved in melanocyte destruction. Several studies including ours have established that oxidative stress is involved in vitiligo onset, while autoimmunity contributes to the disease progression. However, the underlying mechanism involved in programing the onset and progression of the disease remains a conundrum. Based on several direct and indirect evidences, we suggested that endoplasmic reticulum (ER) stress might act as a connecting link between oxidative stress and autoimmunity in vitiligo pathogenesis. Oxidative stress disrupts cellular redox potential that extends to the ER causing the accumulation of misfolded proteins, which activates the unfolded protein response (UPR). The primary aim of UPR is to resolve the stress and restore cellular homeostasis for cell survival. Growing evidences suggest a vital role of UPR in immune regulation. Moreover, defective UPR has been implicated in the development of autoimmunity in several autoimmune disorders. ER stress-activated UPR plays an essential role in the regulation and maintenance of innate as well as adaptive immunity, and a defective UPR may result in systemic/tissue level/organ-specific autoimmunity. This review emphasizes on understanding the role of ER stress-induced UPR in the development of systemic and tissue level autoimmunity in vitiligo pathogenesis and its therapeutics.

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Section: Immunosuppressive Effectsmentioning

confidence: 99%

“…Oncogene mutations will facilitate antigen presentation, which stimulates an anti-tumor immunity to inhibit cancer development and progression. In order to attain the goal of immune escape, cancer cells are supposed to possess strong immunosuppressive capability in the TME that consists of stromal cells and infiltrating immune cells ( Ramirez et al, 2019 ). TERS alter the development of anti-tumor immune responses by inducing ER stress and the UPR in tumor-infiltrating immune cells, including TAMs, bone marrow-derived dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs) and T cells.…”

Section: The Effects Of Ters On Tumor Immunitymentioning

confidence: 99%

Transmissible Endoplasmic Reticulum Stress: A Novel Perspective on Tumor Immunity

Jiang

Zhang

Huang

et al. 2020

Front. Cell Dev. Biol.

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As the first compartment of the protein secretory pathway, the endoplasmic reticulum (ER) acts as a protein synthesis factory, maintaining proteostasis and ER homeostasis. However, a variety of intrinsic and extrinsic perturbations, such as cancer, can disrupt the homeostasis and result in a large accumulation of misfolded/unfolded proteins in the ER lumen, thereby provoking a specific cellular state addressed as "ER stress". Then the unfolded protein response (UPR), an adaptive signaling pathway, is triggered to address the stress and restore the homeostasis. A novel aspect of ER stress is that it can be transmitted from cancer cells to tumor-infiltrating myeloid cells through certain cancer cell-released soluble factors, which is termed as transmissible ER stress (TERS) or ER stress resonance (ERSR). In this review, we provide a comprehensive overview of the link between cancer and ER stress as well as the possible soluble factors mediating TERS. We further elaborate the cell-extrinsic effects of TERS on tumor immunity, and how it indirectly modulates cancer development and progression, which is expected to add a new dimension to anticancer therapy.

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Endoplasmic Reticulum Stress Pathway, the Unfolded Protein Response, Modulates Immune Function in the Tumor Microenvironment to Impact Tumor Progression and Therapeutic Response

Cited by 39 publications

References 177 publications

Tumor-Secreted GRP78 Promotes the Establishment of a Pre-metastatic Niche in the Liver Microenvironment

Tumor-Secreted GRP78 Promotes the Establishment of a Pre-metastatic Niche in the Liver Microenvironment

A Concise Review on the Role of Endoplasmic Reticulum Stress in the Development of Autoimmunity in Vitiligo Pathogenesis

Transmissible Endoplasmic Reticulum Stress: A Novel Perspective on Tumor Immunity

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