The effects of PD-L1 and SCE over-expression on CAR-NK cell cytotoxicity against tumor cells
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PROVIDER: PRJNA1157192 | ENA |
REPOSITORIES: ENA
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Project description:This experiment aims to investigate how the overexpression of PD-L1 and SCE enhances the cytotoxic activity of CAR-NK cells against tumor cells. Pathway enrichment analysis revealed that CAR-NK cells with reduced HLA-ABC and overexpressed PD-L1 showed enrichment in proliferation and pro-inflammatory pathways. In contrast, CAR-NK cells with reduced HLA-ABC and overexpressed SCE exhibited enrichment in homeostasis-related pathways. On the other hand, cellular stress pathways were more prominently enriched in HLA-ABC reduced CAR NK cells following co-culture with target cells.
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Project description:Chimeric antigen receptor (CAR)-NK therapy has emerged as a highly promising alternative to CAR-T cell therapy, due to its remarkable efficacy and safety in hematological tumors. However, the efficacy of CAR-NK cells currently remains limited in solid tumors. Here, we successfully developed CISH locus-specific integrated CAR-NK cells using a non-viral mini-circular single-stranded DNA (mcssDNA)-based CRISPR/Cas9 targeted genome editing (mcssDNA/CRISPR/Cas9) technology via a single-step electroporation procedure. The developed CISH-knockout (CISH-KO) CAR-NK cells exhibited the enhanced proliferation and cytotoxicity against hepatocellular carcinoma (HCC) compared with conventional lentivirus-transduced CAR-NK (LV-CAR-NK) cells. Single-cell RNA sequencing analysis revealed an important subset of adaptive NK cells that were highly enriched in CISH-KO CAR-NK cells compared to LV-CAR-NK cells and showed the up-regulated JAK/STAT, energy metabolism and activating receptor signaling. Furthermore, non-viral CISH locus-specific integrated IL-15-armored CAR-NK cells were generated and achieved persistent tumor regression and a significant survival advantage in a lung metastatic mouse model of HCC. Collectively, our results demonstrate that non-viral CISH locus-specific integrated CAR-NK cells can be generated by a simplified, single-step manufacturing procedure and achieve potent efficacy against HCC, thus providing an innovative technology for CAR-NK cell therapy against solid tumors.
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