RELB Reprograms Exhausted Tumor-Infiltrating Lymphocytes for Improved Adoptive Cell Therapy

Area of Science:

• Immunology
• Cell Therapy
• Cancer Research

Background:

• Tumor-infiltrating lymphocytes (TILs) are a promising cell therapy for solid tumors.
• Current TIL therapies face challenges due to T cell dysfunction and limited expansion.
• CD103+CD39+ CD8+ TILs show tumor reactivity but often exhibit exhaustion.

Purpose of the Study:

• To identify regulators of human TIL proliferation.
• To enhance the efficacy of TIL-based cancer immunotherapy.

Main Methods:

• Screened a human transcription factor library to find TIL expansion regulators.
• Utilized co-culture models with tumor organoids and HER2-targeting CAR T cells.
• Performed transcriptome profiling and *in vivo* mouse xenograft studies.

Main Results:

• RELB was identified as a key driver of human TIL expansion, particularly CD8+ T cells.
• RELB expression maintained T cell receptor diversity and promoted a memory phenotype.
• RELB-engineered TILs demonstrated enhanced persistence, tumor control in vivo, and improved killing of patient-matched tumor organoids.

Conclusions:

• RELB acts as a potent regulator of TIL proliferation and function.
• Promoting RELB expression is a viable strategy to enhance TIL therapy for solid tumors.
• This approach could broaden the applicability and effectiveness of TIL-based immunotherapies.