Targeting Regnase-1 unleashes CAR T cell antitumor activity for osteosarcoma and creates a proinflammatory tumor...

Area of Science:

• Immunology
• Cancer Biology
• Cell Therapy

Background:

• Negative regulators of T cell function are targets for enhancing CAR T cell therapy against solid tumors.
• The immunosuppressive tumor microenvironment poses a barrier to CAR T cell efficacy.
• The impact of deleting negative regulators on the tumor immune landscape is not well understood.

Purpose of the Study:

• To investigate the effects of deleting Regnase-1 (Reg-1) in B7-H3 CAR T cells.
• To determine if Reg-1 deletion in CAR T cells can overcome the immunosuppressive tumor microenvironment.
• To evaluate the intrinsic and extrinsic effects of Reg-1 deletion on CAR T cell function and the tumor immune landscape.

Main Methods:

• Development of CAR T cells targeting B7-H3.
• Deletion of the negative regulator Regnase-1 (Reg-1) in CAR T cells.
• Evaluation of CAR T cell effector function in immune-competent osteosarcoma models.
• Analysis of the tumor microenvironment composition and cytokine production.

Main Results:

• Reg-1 deletion improved the intrinsic effector function of B7-H3 CAR T cells.
• Reg-1 deletion promoted a proinflammatory tumor microenvironment.
• CAR T cells with Reg-1 deletion induced an influx of IFNγ-producing T cells and NK cells.
• Reg-1 deletion led to a reduction in inhibitory myeloid cells, including M2 macrophages.

Conclusions:

• Deleting negative regulators like Reg-1 in CAR T cells enhances their antitumor activity.
• CAR T cells engineered to lack Reg-1 can reprogram the tumor microenvironment towards a proinflammatory state.
• This strategy enforces a non-cell-autonomous effect, improving CAR T cell therapy for solid tumors.