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

Area of Science:

• Immunology
• Cancer Biology
• Proteostasis

Background:

• Tumor-infiltrating lymphocytes (TIL) often become terminally exhausted, failing to control tumor growth.
• Tissue-resident memory T cells (T_RM) exhibit features associated with better patient prognosis in tumors.
• Proteostasis, the regulation of protein homeostasis, is critical for T cell function and longevity.

Purpose of the Study:

• To investigate the role of proteostasis in distinguishing functional TIL from exhausted TIL.
• To identify key molecular players, such as E3 ubiquitin ligases, involved in proteostasis.
• To explore the therapeutic potential of restoring proteostasis in TIL for cancer immunotherapy.

Main Methods:

• Proteomic and transcriptomic profiling of T cell populations.
• Analysis of E3 ubiquitin ligases (NEURL3, RNF149, WSB1) and protein accumulation.
• Functional assays in preclinical models of tumors and chronic/acute infections.
• Enforced expression of E3 ligases in T cells.

Main Results:

• Terminally exhausted TIL show reduced expression of NEURL3, RNF149, and WSB1, leading to unfolded protein accumulation.
• Enforced expression of these ligases preserved stem-like TCF1⁺ TIL populations and enhanced anti-tumor function.
• Restoring ligase expression improved TIL function in tumors and chronic infections, and enhanced immunotherapy outcomes.

Conclusions:

• Proteostasis, regulated by E3 ubiquitin ligases, is crucial for maintaining TIL function and preventing exhaustion.
• Targeting proteostasis pathways offers a promising strategy to enhance TIL-mediated anti-tumor immunity.
• Restoring E3 ligase activity in TIL represents a novel therapeutic avenue for improving cancer immunotherapy.