Background Adoptive cell therapy has emerged as a promising immunotherapeutic approach to fight cancers. This approach involves genetically engineering immune cells to express a surface receptor known as Chimeric Antigen Receptor (CAR), which is designed to specifically target antigens present on the surface of tumor cells. CAR-Natural Killer (CAR-NK) cells were introduced as a complement alternative to other CAR engineered cell therapy for solid tumors since they do not require HLA compatibility and might be generated in large scale for the ‘off-the-shelf’.
Solid tumors represent a significant challenge in cancer therapy due to their intricate microenvironment and immunosuppressive nature. The tumor cells that enriched their surrounding microenvironment with TGF-β, can induce the NK cell conversion toward the less cytotoxic function. In this study, we focused on the microenvironment with TGF-β of solid tumors and designed a TGF-β receptor inhibitory peptide (UP01a) that can disrupt TGF-β signaling pathway.
Methods We used a VSV-G pseudotyped lentiviral vector system to transduce primary human NK cells with a CAR construct specific for a tumor-associated antigen expressed on solid tumors. The effect of UP01a on tumor cells was assessed by western blotting. To evaluate their therapeutic efficacy, we utilized in vitro 2D co-culture assays for cytotoxicity and established 3D spheroid model preserves the tumor microenvironment (TME) for NK cell infiltration. Also in vivo efficacy was subsequently evaluated with xenograft mouse models.
Results Our findings demonstrated that the engineered CAR-NK cells were modified to secrete UP01a, enabling them to disrupt the TGF-β signaling pathway of the CAR-NK itself within the TME. Additionally, UP01a-secreted CAR-NK cells were enhanced cytotoxicity against solid tumor cells compared to Naïve NK or CAR-NK cells alone. Furthermore, UP01a secretion significantly reduced TGF-β induced immunosuppressive factors and increased the NK cell infiltration within the TME. Moreover, the administration of UP01a-secreted CAR-NK cells led to a substantial reduction in tumor growth, and histopathological analysis revealed increasing of tumor cell apoptosis and necrosis.
Conclusions Overall, our results demonstrate that the UP01a-secreted CAR-NK cells enhanced their cytotoxic efficacy by reducing the immunosuppressive effects of TGF-β. This innovative approach holds great promise for the development of more effective immunotherapies for solid tumors, deserving further investigation for its clinical translation.
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