RASA2 ablation in T cells boosts antigen sensitivity and long-term function.

Area of Science:

• Immunology
• Cancer Biology
• Gene Editing

Background:

• Adoptive T cell therapy efficacy is limited by immunosuppressive signals and intrinsic inhibitory checkpoints.
• Targeted gene editing offers a strategy to overcome these limitations and enhance T cell function.

Purpose of the Study:

• To identify genes that can be targeted to prevent T cell dysfunction using genome-wide CRISPR screens under immunosuppressive conditions.
• To investigate the role of RASA2 as a signaling checkpoint in human T cells and its potential as a therapeutic target.

Main Methods:

• Performed multiple genome-wide CRISPR knock-out screens under various immunosuppressive conditions.
• Investigated RASA2's role in T cell signaling and function, including MAPK signaling and CAR T cell activity.
• Evaluated the efficacy of RASA2 ablation in preclinical models of T cell receptor and CAR T cell therapies.

Main Results:

• Screens converged on RASA2, a RAS GTPase-activating protein (RasGAP), identified as a T cell signaling checkpoint.
• RASA2 ablation enhanced MAPK signaling and chimeric antigen receptor (CAR) T cell cytolytic activity.
• RASA2-deficient T cells exhibited increased activation, cytokine production, metabolic activity, and enhanced persistent cancer cell killing.
• RASA2-knockout CAR T cells showed competitive fitness advantage in vivo, and RASA2 ablation prolonged survival in preclinical models.

Conclusions:

• RASA2 is a promising target for enhancing T cell persistence and effector function in cancer therapy.
• Targeting RASA2 can overcome T cell dysfunction and improve outcomes in adoptive T cell therapies.
• Gene editing strategies targeting RASA2 hold potential for developing more effective cancer treatments.