Stress-Mediated Attenuation of Translation Undermines T-cell Activity in Cancer

Area of Science:

• Immunology
• Cancer Biology
• Molecular Biology

Background:

• Protein synthesis is crucial for effective immune responses.
• The tumor microenvironment (TME) presents stressors like nutrient competition that can inhibit T cell function.
• Understanding how T cell protein translation is affected in the TME is vital for improving cancer immunotherapy.

Purpose of the Study:

• To investigate the impact of the TME on T cell protein translation.
• To identify mechanisms regulating T cell protein translation in solid tumors.
• To explore therapeutic strategies to enhance T cell function in cancer.

Main Methods:

• Analysis of human and mouse tumors to assess T cell protein translation.
• Utilizing genetic mouse models to study the role of the unfolded protein response (UPR) element eIF2α.
• Employing metabolic and pharmacological approaches to modulate T cell function and proteasome activity.

Main Results:

• Protein translation is significantly repressed in T cells within solid tumors.
• Reduced glucose in the TME activates the UPR element eIF2α (eukaryotic translation initiation factor 2 alpha), leading to translation attenuation.
• Activated p-eIF2α impairs T cell-mediated tumor suppression.
• Reprogramming T cell metabolism and enhancing proteasome activity alleviate p-eIF2α accumulation and restore protein translation.
• These interventions support sustained cytokine synthesis and optimal antitumor T cell function.

Conclusions:

• T cell protein translation is a critical target in the TME.
• The UPR, mediated by eIF2α, plays a key role in suppressing T cell function in tumors.
• Metabolic reprogramming and proteasome modulation represent promising therapeutic strategies to enhance T cell-based cancer immunotherapy.