Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes

Ignazio Caruana, Barbara Savoldo, Valentina Hoyos, Gerrit Weber, Hao Liu, Eugene S. Kim, Michael M. Ittmann, Dario Marchetti, Gianpietro Dotti

Research output: Contribution to journalArticle

Abstract

Adoptive transfer of chimeric antigen receptor (CAR)-redirected T lymphocytes (CAR-T cells) has had less striking therapeutic effects in solid tumors than in lymphoid malignancies. Although active tumor-mediated immunosuppression may have a role in limiting the efficacy of CAR-T cells, 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.

Original languageEnglish
Pages (from-to)524-529
Number of pages6
JournalNature Medicine
Volume21
Issue number5
DOIs
Publication statusPublished - May 1 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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  • Cite this

    Caruana, I., Savoldo, B., Hoyos, V., Weber, G., Liu, H., Kim, E. S., Ittmann, M. M., Marchetti, D., & Dotti, G. (2015). Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nature Medicine, 21(5), 524-529. https://doi.org/10.1038/nm.3833