Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy.

Area of Science:

• Immunology
• Cancer Biology
• Molecular Biology

Background:

• Adoptive cell therapy (ACT) is a promising cancer immunotherapy.
• Poor persistence and function of transferred T cells limit ACT efficacy.

Purpose of the Study:

• To identify genetic targets that enhance T cell persistence and function for improved ACT.
• To investigate the role of REGNASE-1 in regulating CD8+ T cell effector function and longevity.

Main Methods:

• In vivo pooled CRISPR-Cas9 mutagenesis screening to identify genes regulating T cell function.
• Secondary genome-scale CRISPR-Cas9 screening to identify downstream targets.
• Evaluation of REGNASE-1 deficient CD8+ T cells in mouse models of melanoma and leukemia.

Main Results:

• Targeting REGNASE-1 reprogrammed CD8+ T cells into long-lived effector cells with enhanced accumulation, persistence, and anti-tumor function.
• REGNASE-1 deficiency significantly improved therapeutic efficacy in melanoma and leukemia mouse models.
• BATF was identified as a key downstream target of REGNASE-1, regulating T cell accumulation and mitochondrial fitness.
• Targeting additional factors like PTPN2 and SOCS1 further enhanced the efficacy of REGNASE-1 deficient T cells.

Conclusions:

• REGNASE-1 is a critical regulator of T cell persistence and effector function in anti-tumor immunity.
• Targeting REGNASE-1 and associated factors offers a novel strategy to improve adoptive cell therapy for cancer.
• Findings provide avenues for enhancing T cell-based cancer treatments.