CX3CR1 deficiency-induced TIL tumor restriction as a novel addition for CAR-T design in solid malignancies

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Chimeric antigen receptor T-cell (CAR-T) therapy shows promise in treating blood cancers but faces challenges in solid tumors due to limited infiltration.
• Understanding the tumor microenvironment is crucial for developing effective immunotherapies for solid malignancies.

Purpose of the Study:

• To investigate the mechanisms restricting cytotoxic lymphocyte infiltration in non-small-cell lung cancer (NSCLC).
• To design and evaluate an improved CAR-T construct for enhanced infiltration and efficacy in solid tumors.

Main Methods:

• Analysis of receptor expression in normal, adjacent, and tumor tissues from primary NSCLC specimens.
• Development of a novel CAR-T construct combining natural killer group 2, member D (NKG2D) CAR-T with CX3CR1 overexpression.
• Comparison of infiltration rates and functionality of engineered CAR-Ts versus control T-cells and IL-15-overexpressing NKG2D CAR-Ts in vitro and in vivo models.

Main Results:

• Reduced CX3CL1-CX3CR1 signaling was identified as a key factor limiting cytotoxic cell infiltration into solid tumors.
• The novel CX3CR1-overexpressing NKG2D CAR-Ts demonstrated significantly higher infiltration rates into NSCLC tumors compared to controls.
• The engineered CAR-Ts exhibited potent anti-tumor functionality in both NSCLC and liver cancer models.

Conclusions:

• CX3CL1-CX3CR1 axis modulation is a viable strategy to enhance CAR-T cell infiltration in solid tumors.
• Engineered CAR-Ts with CX3CR1 overexpression represent a promising therapeutic approach for treating lung and other solid malignancies.
• This strategy holds potential for broader application in solid tumor immunotherapy.