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CAR-redirected T lymphocytes

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发表于 2015-8-25 09:41:37 | 显示全部楼层 |阅读模式
Adoptive transfer of chimeric antigen receptor (CAR)-redirectedT lymphocytes (CAR-T cells) has had less striking therapeuticeffects in solid tumors1–3 than in lymphoid malignancies4,5.Although active tumor-mediated immunosuppression may have a role in limiting the efficacy of CAR-T cells6, functional changes in T lymphocytes after theirex vivo manipulation may also account for the reduced ability of cultured CAR-T cells to
penetrate stroma-rich solid tumors compared with lymphoidtissues. We therefore studied the capacity of human in vitrocultured CAR-T cells to degrade components of the extracellular matrix (ECM). In contrast to freshly isolated T lymphocytes,we found that in vitro–cultured T lymphocytes lack expression of the enzyme heparanase (HPSE), which degrades heparan sulfate proteoglycans, the main components of ECM. We found
that HPSE mRNA is downregulated in in vitro–expanded T cells,which may be a consequence of p53 (officially known as TP53, encoding tumor protein 53) binding to the HPSE gene promoter. We therefore engineered CAR-T cells to express HPSE and showed their improved capacity to degrade the ECM, which promoted tumor T cell infiltration and antitumor activity. The use of this strategy may enhance the activity of CAR-T cells in
individuals with stroma-rich solid tumors.
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