Proteostasis sustains T cell differentiation potential and tumor-infiltrating lymphocyte function

Area of Science:

• Immunology
• Cancer Biology
• Proteostasis

Background:

• Tumor-infiltrating lymphocytes (TIL) often exhibit an exhausted phenotype, limiting their anti-tumor efficacy.
• Tissue-resident memory T cells (T_RM) provide long-term protection and are associated with better patient prognosis when present in tumors.

Purpose of the Study:

• To investigate the role of proteostasis in T cell function and differentiation.
• To identify molecular mechanisms underlying TIL exhaustion and T_RM maintenance.
• To explore therapeutic strategies for improving anti-tumor immunity by targeting proteostasis.

Main Methods:

• Proteomic and transcriptomic profiling of T cell populations.
• Analysis of E3 ubiquitin ligase expression (NEURL3, RNF149, WSB1) in TIL and T_RM.
• Functional assays assessing TIL anti-tumor activity and T cell differentiation.
• Preclinical models of cancer immunotherapy.

Main Results:

• Loss of specific E3 ubiquitin ligases (NEURL3, RNF149, WSB1) in TIL correlates with proteostasis defects and protein unfolding.
• Enforced expression of these ligases preserved stem-like TIL populations and enhanced anti-tumor function.
• Ligase knockout impaired TIL function and altered T cell differentiation during infection.
• Restoring ligase expression improved immunotherapy outcomes in preclinical cancer models.

Conclusions:

• Proteostasis, regulated by E3 ubiquitin ligases, is critical for maintaining TIL function and preventing exhaustion.
• Targeting proteostasis pathways offers a promising strategy for enhancing cancer immunotherapy.
• Restoring E3 ligase expression can rescue TIL function and improve anti-tumor responses.