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Dihydroartemisinin enhances NKG2D CAR-T cell therapy against solid tumors by inducing NKG2D ligands and remodeling
Muhammad Auwal Saliu1, Mansur Dabai Salisu1, Rabiatu Bako Suleiman1
1Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Abstract:
Despite the clinical approval of CAR-T cell therapies for hematological malignancies, their success in solid tumors remains limited due to several factors including antigen escape, immunosuppressive tumor microenvironment (TME), and poor T-cell trafficking to the tumor site. NKG2D CAR-T cells, recognizing multiple stress-inducible NKG2D ligands (NKG2DLs), offer a promising but modest antitumor benefit. Pharmacological agents capable of enhancing NKG2DLs expression and remodeling the TME may overcome these barriers. Here, we identified dihydroartemisinin (DHA), a clinically approved antimalarial compound as a novel inducer of NKG2DLs in tumor cells at non-cytotoxic concentrations without affecting primary human T cells. Transcriptomic analysis revealed that this effect involves activation of DNA damage response, p53, and PI3K/Akt signaling pathways. In addition, DHA upregulated MHC-I and suppressed B7-H3 expression, promoted secretion of T-cell-recruiting chemokines (CXCL9, CXCL10), and polarized macrophages toward an M1-like phenotype, thus contributes to an immunostimulatory TME. Functionally, DHA pretreatment of tumor cells significantly enhanced NKG2D CAR-T cell activation, trafficking, and cytotoxicity. In pancreatic and prostate xenograft models, DHA combined with NKG2D CAR-T cells increased intratumoral T-cell infiltration which led to significant tumor control without any systemic toxicity. This study provides the first evidence that DHA upregulates tumor NKG2DLs and reprograms the TME through modulation of tumor immune axis. Our findings establish DHA as a clinically accessible pharmacological adjuvant with strong translational potential to improve NKG2D CAR-T therapy against solid tumors.
Insights
Dihydroartemisinin (DHA) enhances NKG2D CAR-T cell therapy for solid tumors by increasing tumor cell NKG2D ligand expression and reprogramming the tumor microenvironment (TME) for improved T-cell function and tumor control.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- CAR-T cell therapy shows promise for hematological cancers but faces challenges in solid tumors, including antigen escape, immunosuppressive tumor microenvironment (TME), and poor T-cell trafficking.
- NKG2D CAR-T cells target stress-inducible ligands (NKG2DLs) for modest antitumor effects, necessitating strategies to enhance their efficacy.
Purpose of the Study:
- To identify pharmacological agents that can upregulate NKG2DLs and remodel the TME to overcome limitations of CAR-T cell therapy in solid tumors.
- To investigate the potential of dihydroartemisinin (DHA) as an adjuvant for NKG2D CAR-T cell therapy.
Main Methods:
- Identified DHA as an inducer of NKG2DLs in tumor cells at non-cytotoxic concentrations.
- Utilized transcriptomic analysis to elucidate the molecular pathways involved in DHA's effects.
- Assessed DHA's impact on MHC-I, B7-H3 expression, chemokine secretion, macrophage polarization, and T-cell recruitment in vitro and in vivo models.
- Evaluated the efficacy of combining DHA with NKG2D CAR-T cells in pancreatic and prostate cancer xenograft models.
Main Results:
- DHA upregulated NKG2DLs in tumor cells via DNA damage response, p53, and PI3K/Akt pathways without affecting T cells.
- DHA modulated the tumor immune axis by upregulating MHC-I, suppressing B7-H3, promoting T-cell-recruiting chemokines, and polarizing macrophages to an M1-like phenotype, creating an immunostimulatory TME.
- DHA pretreatment enhanced NKG2D CAR-T cell activation, trafficking, and cytotoxicity.
- Combination therapy with DHA and NKG2D CAR-T cells significantly controlled tumor growth in xenograft models with no systemic toxicity.
Conclusions:
- DHA effectively upregulates tumor NKG2DLs and reprograms the TME, enhancing NKG2D CAR-T cell therapy against solid tumors.
- DHA demonstrates strong translational potential as a clinically accessible pharmacological adjuvant to improve CAR-T cell therapy outcomes in solid tumors.
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