Endoplasmic Reticulum Stress Contributes to Mitochondrial Exhaustion of CD8⁺ T Cells

Area of Science:

• Immunology
• Cancer Biology
• Cellular Metabolism

Background:

• Tumor-infiltrating lymphocytes (TILs) exhibit diminished energy and effector function within the tumor microenvironment.
• The precise cellular mechanisms driving T cell exhaustion and energy depletion in tumors remain poorly understood.
• Identifying tumor antigen-specific TILs experiencing stress is crucial for developing effective immunotherapies.

Purpose of the Study:

• To investigate the role of endoplasmic reticulum (ER) stress, specifically the PERK-ERO1α pathway, in T cell energy depletion.
• To determine if targeting ER stress can enhance T cell function and improve anti-tumor immunity.
• To identify biomarkers of ER-induced mitochondrial exhaustion in T cells.

Main Methods:

• Generated T-cell-specific PERK knockout (PERK KO) mice (OT1 Lckcre PERK).
• Utilized pharmacological inhibitors of PERK and ERO1α in T cells.
• Assessed T cell energy reserves, protein profiles, mitochondrial reactive oxygen species (mtROS), and tumor control in vivo.

Main Results:

• PERK KO T cells and pharmacologically inhibited T cells showed preserved energy and reduced oxidative stress.
• These T cells demonstrated superior tumor control compared to standard T effectors.
• Mitochondrial ROS (mtROS) was identified as a biomarker for ER-induced mitochondrial exhaustion in TILs, elevated in PD-1+ CD8+ TILs.
• In vivo PERK inhibition reduced mtROS in PD-1+ CD8+ TILs, enhancing their viability and leading to significant tumor clearance and survival in a sarcoma model.

Conclusions:

• The endoplasmic reticulum (ER) significantly regulates T cell energetics and function.
• Targeting ER stress pathways, such as PERK-ERO1α, is a viable strategy to enhance T cell-mediated anti-tumor immunity.
• mtROS serves as a key biomarker for ER-induced mitochondrial exhaustion in T cells, offering a target for therapeutic intervention.