ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis

Area of Science:

• Immunology
• Cancer Biology
• Cellular Stress Response

Background:

• Myeloid-derived suppressor cells (MDSCs) are key regulators of immune suppression in cancer.
• MDSCs are known to expand in pathological conditions, including cancer, contributing to tumor progression.
• The precise mechanisms regulating MDSC lifespan and expansion in cancer remain incompletely understood.

Purpose of the Study:

• To investigate the factors influencing the viability and half-life of MDSCs in a tumor microenvironment.
• To explore the role of TNF-related apoptosis-induced ligand receptors (TRAIL-Rs) and endoplasmic reticulum (ER) stress in MDSC pathophysiology.
• To evaluate TRAIL-Rs as potential therapeutic targets for modulating MDSC populations in cancer.

Main Methods:

• Comparative analysis of MDSC viability and half-life versus neutrophils and monocytes in tumor-bearing mice.
• Assessment of TRAIL-R expression and its correlation with apoptosis in MDSCs.
• In vivo studies targeting TRAIL-Rs in naive and tumor-bearing mice.
• Investigation of the impact of proinflammatory cytokines and ER stress induction on TRAIL-R expression in myeloid cells.
• Analysis of ER stress markers in MDSCs from cancer patients and tumor-bearing mice.

Main Results:

• MDSCs exhibited significantly lower viability and a shorter half-life in tumor-bearing mice compared to other myeloid cells.
• Increased apoptosis in MDSCs was linked to elevated expression of TRAIL-Rs.
• Targeting TRAIL-Rs reduced MDSC presence and enhanced immune responses in tumor-bearing mice.
• ER stress was identified in MDSCs from cancer patients and tumor-bearing mice, correlating with TRAIL-R expression.
• Blockade of ER stress reversed tumor-associated changes in TRAIL-R expression.

Conclusions:

• MDSC pathophysiology in cancer is associated with ER stress, leading to reduced peripheral lifespan.
• Increased TRAIL-R expression, driven by ER stress, contributes to MDSC apoptosis.
• TRAIL-Rs represent a promising therapeutic target for selective inhibition of MDSCs in cancer settings.
• Understanding the link between ER stress and MDSC fate provides insights into immune evasion mechanisms in cancer.