Journal
NATURE MEDICINE
Volume 21, Issue 5, Pages 524-U158Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3833
Keywords
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Funding
- US National Institutes of Health-National Cancer Institute [R01 CA142636]
- Department of Defense
- Technology and Therapeutic Development Award [W81XWH-10-10425]
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Adoptive transfer of chimeric antigen receptor (CAR)-redirected T lymphocytes (CAR-T cells) has had less striking therapeutic effects in solid tumors(1-3) than in lymphoid malignancies(4,5). Although active tumor-mediated immunosuppression may have a role in limiting the efficacy of CAR-T cells(6), functional changes in T lymphocytes after their ex vivo manipulation may also account for the reduced ability of cultured CAR-T cells to penetrate stroma-rich solid tumors compared with lymphoid tissues. We therefore studied the capacity of human in vitro-cultured 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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