DAP10 integration in CAR-T cells enhances the killing of heterogeneous tumors by harnessing endogenous NKG2D

Area of Science:

• Immunotherapy
• Oncology
• Molecular Biology

Background:

• Chimeric antigen receptor T (CAR-T) cell therapy shows promise in hematological cancers but faces challenges in solid tumors due to heterogeneous antigen expression.
• Natural killer group 2D (NKG2D) and its adaptor DNAX-activating protein 10 (DAP10) play a role in targeting malignant cells.
• Glypican 3 (GPC3) is a cell surface antigen often found on solid tumors.

Purpose of the Study:

• To engineer a novel dual-targeting CAR-T cell system to overcome antigen heterogeneity in solid tumors.
• To leverage the DAP10 adaptor and NKG2D receptor for enhanced T cell surveillance.
• To combine DAP10-mediated targeting with GPC3-specific targeting for improved cancer cell elimination.

Main Methods:

• Designed a chimeric receptor utilizing DAP10 to engage native NKG2D on T cells.
• Constructed a dual-targeting system by tandemly incorporating an anti-GPC3 single-chain variable fragment (scFv) with the DAP10 chimeric receptor.
• Evaluated the efficacy of engineered T cells (DAP10-T and CAR GPC3-DAP10-T cells) in vitro and in vivo against solid cancer models.

Main Results:

• DAP10-T cells demonstrated enhanced cytotoxicity and cytokine secretion against solid cancer cell lines.
• CAR GPC3-DAP10-T cells exhibited dual-antigen targeting, effectively eliminating heterogeneous cancer cells in vitro.
• The dual-targeting CAR-T system suppressed tumor growth in vivo, indicating significant therapeutic potential.

Conclusions:

• The novel dual-targeting system broadens the recognition profile of CAR-T cells for solid tumors.
• This strategy enhances the efficacy of CAR-T cell therapy against heterogeneous solid cancers.
• This approach offers a promising new avenue for the clinical treatment of solid tumors.