B cells enhanced the anti-U251/U373 activity of EphA2-CAR T cells
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PROVIDER: PRJNA915028 | ENA |
REPOSITORIES: ENA
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Project description:Chimeric antigen receptor (CAR) T cell therapy is a powerful adoptive immunotherapy against blood cancers, but the therapeutic effect was not efficient enough on solid tumors. B cells have been reported to play a critical role in regulating memory T differentiation and cytotoxic T development. However, as of yet the influence of such B cells on CAR T cells has not been discussed. In this study, using ephrin type-A receptor 2 (EphA2) specific CAR T cells, we cultured B cells successfully to stimulate T cells in vitro, and investigated the cell differentiation and anti-tumor efficiency. We observed that EphA2-CAR T cells stimulated by B cells performed enhanced anti-tumor ability with more interferon γ (IFN γ) production and higher OX40 expression. The differentiation of CAR T cells was arrested after B cells stimulation for more than 7 days with the percentage of central memory T cells (Tcm) increasing. In addition, next generation sequencing was performed. The top expressed genes clustered in activation, leukocyte migration and chemokine signaling pathway contributed to the anti-glioblastoma (GBM) activity of CAR T cells stimulated by B cell. In conclusion, these results indicated the importance of B cells in retarding CAR T cells differentiation and enhancing anti-tumor activity, which paves the way for the rapid exploitation of EphA2-CAR T cells against GBM in the future.
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Project description:Chimeric antigen receptor (CAR) T cell therapy is a promising immunotherapy against cancer. Although there is a growing interest in other cell types, a comparison of CAR immune effector cells in challenging solid tumor contexts is lacking. Here, we compare mouse and human NKG2D-CAR expressing T cells, NK cells and macrophages against glioblastoma, the most aggressive primary brain tumor. In vitro we show that T cell cancer killing is CAR-dependent, whereas intrinsic cytotoxicity overrules CAR-dependence for NK cells and CAR macrophages reduce glioma cells in co-culture assays. In orthotopic immunocompetent glioma mouse models, systemically administered CAR T cells demonstrate superior accumulation in the tumor and each immune cell type induces distinct changes in the tumor microenvironment. An otherwise low therapeutic efficacy is significantly enhanced by co-expression of pro-inflammatory cytokines in all CAR immune effector cells, underscoring the necessity for multifaceted cell engineering strategies to overcome the immunosuppressive solid tumor microenvironment.
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Project description:Ewing sarcoma (ES) is the second most common bone malignancy affecting children and young adults with poor prognosis due to high metastasis incidence. Our group previously described that EphA2, a tyrosine kinase receptor, promotes angiogenesis in ES cells via ligand-dependent signaling. EphA2 ligand-independent activity, controlled upon phosphorylation at S897 (p-EphA2S897), has been linked to metastasis in several malignancies. Here, we stablish a correlation between ES cells aggressiveness and p-EphA2S897. Moreover, stable overexpression of EphA2 in low EphA2 expression ES cells enhanced proliferation and migration, but not a nonphosphorylable mutant (S987A). Consistently, silencing of EphA2 reduced tumorigenicity, migration and invasion in vitro, and lung metastasis incidence in experimental and spontaneous metastasis assays in vivo. A gene expression microarray revealed the implication of EphA2 in cell signaling, cellular movement and survival. Altogether, our results suggest that p-EphA2S897 correlates with aggressiveness in ES, so blocking its function may be a promising treatment.
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Project description:VHL mutations are the most common tumorigenic lesions in clear cell renal cell carcinoma (ccRCC) and result in continued activation of the HIF/VEGF pathway and uncontrolled cancer progression. Receptor tyrosine kinase (RTK) inhibitors such as sunitinib have been demonstrated to target tumorigenic signaling pathways, delay tumor progression and improve patient prognosis in metastatic renal cell carcinoma (mRCC). Although several mechanisms of sunitinib resistance have been reported, the solutions to overcome this resistance remain still unclear. In our study, we found that increased expression of YB1 (Y box binding protein 1, a multidrug resistance associated protein) and EphA2 (a member of erythropoietin-producing hepatocellular (Eph) receptors, belonging to the RTK family) mediated sunitinib resistance and mRCC exhibited a large phenotypic dependence on YB1 and EphA2. In addition, our findings confirm that YB1 promotes the invasion, metastasis and sunitinib resistance of ccRCC by regulating the EphA2 signaling pathway. Furthermore, pharmacological inhibition of EphA2 through the small molecule inhibitor ALW-II-41-27 reduced the proliferation of sunitinib-resistant tumor cells and suppressed tumor growth in vivo and restored the sensitivity of sunitinib-resistant tumor cells to sunitinib in vitro and in vivo. Mechanistically, YB1 increases the protein levels of EphA2 by maintaining the protein stabilization of EphA2 through inhibiting the proteasomal degradation pathway. Collectively, our findings provide the theoretical rationale that ccRCC metastasis and RTK-directed therapeutic resistance could be prospectively and purposefully targeted.
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Project description:We used Crispr/Cas9 technology to establish a homozygous clone of EphA2-SE deletion in tumor cells. Wild-type cells (WT) and homozygous cloned cells (EphA2-SE-/-) were selected for high-throughput data detection.
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