CAR T-cell Entry into Tumor Islets Is a Two-Step Process Dependent on IFNγ and ICAM-1.

Area of Science:

• Immunotherapy
• Oncology
• Cellular Therapy

Background:

• Adoptive T-cell therapy with chimeric antigen receptors (CAR) is effective against B-cell cancers.
• CAR T-cell efficacy against solid tumors remains limited.
• Understanding CAR T-cell tumor infiltration is crucial for improving solid tumor therapy.

Purpose of the Study:

• To compare the early functional responses of CD20 and EGFR CAR T-cells against malignant B cells and carcinoma cells.
• To elucidate the mechanisms governing CAR T-cell infiltration into solid tumors.
• To identify strategies for enhancing CAR T-cell therapy for solid tumors.

Main Methods:

• Fluorescent imaging microscopy and ex vivo assays.
• Analysis of CAR T-cell migration, calcium signaling, and cytotoxicity.
• Interference with ICAM-1/LFA-1 interactions using antibody or shRNA blockade.

Main Results:

• CD20 CAR T-cells formed rapid, ICAM-1-dependent conjugates with B-cell targets.
• EGFR CAR T-cells exhibited a two-step infiltration process into solid tumors: initial peripheral interaction followed by central relocation.
• Activated CAR T-cells induced tumor cell ICAM-1 upregulation via an IFNγ-dependent pathway, facilitating T-cell enrichment.
• Blocking ICAM-1/LFA-1 interactions inhibited CAR T-cell infiltration into tumor islets.

Conclusions:

• CAR T-cell infiltration into solid tumors is a multi-step process dependent on IFNγ and ICAM-1.
• Targeting the IFNγ-ICAM-1 pathway may enhance CAR T-cell therapy for solid tumors.
• This study provides insights into overcoming barriers to CAR T-cell efficacy in solid malignancies.