ULBP2 CAR-T cells enhance gastric cancer immunotherapy by inhibiting CAF activation

Area of Science:

• Oncology
• Immunotherapy
• Cancer Biology

Background:

• Gastric cancer (GC) presents a dense stromal microenvironment and limited therapeutic targets, resulting in poor patient prognosis.
• The tumor microenvironment in GC often hinders effective treatment strategies.

Purpose of the Study:

• To identify novel therapeutic targets for gastric cancer.
• To investigate the role of UL16 binding protein 2 (ULBP2) in GC progression and its potential as a therapeutic target.
• To evaluate the efficacy of ULBP2-targeted chimeric antigen receptor T (CAR-T) cell therapy in preclinical GC models.

Main Methods:

• Identification of ULBP2 as a target in GC.
• Investigation of ULBP2's mechanism involving TGF-β signaling and cancer-associated fibroblasts (CAFs).
• Development and assessment of ULBP2 CAR-T cells in GC cell lines, organoids, CDX, and PDX mouse models, including combination therapy with anti-PD-1 antibodies.

Main Results:

• ULBP2 overexpression activates the TGF-β pathway, leading to CAF activation and promoting GC tumor progression.
• ULBP2 CAR-T cells demonstrated potent elimination of GC cell lines and organoids.
• ULBP2 CAR-T cells, alone or combined with anti-PD-1, significantly inhibited tumor growth and prolonged survival in both CDX and PDX models.

Conclusions:

• ULBP2 promotes GC progression through TGF-β-mediated CAF activation, contributing to a dense stromal microenvironment.
• Targeting ULBP2 with CAR-T cells effectively suppresses tumor growth, reduces stromal deposition, and enhances T cell infiltration.
• ULBP2-targeted therapy holds significant potential for improving gastric cancer treatment outcomes and enhancing immunotherapy efficacy.