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

169 Citations (Scopus)

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 (US)
Pages (from-to)524-529
Number of pages6
JournalNature Medicine
Volume21
Issue number5
DOIs
StatePublished - May 1 2015
Externally publishedYes

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Antigen Receptors
T-cells
T-Cell Antigen Receptor
Infiltration
Tumors
T-Lymphocytes
Neoplasms
Extracellular Matrix
Heparan Sulfate Proteoglycans
Adoptive Transfer
Lymphoid Tissue
Therapeutic Uses
heparanase
Protein Binding
Immunosuppression
Genes
Tissue
Down-Regulation
Messenger RNA
Enzymes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Caruana, I., Savoldo, B., Hoyos, V., Weber, G., Liu, H., Kim, E. S., ... 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

Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. / Caruana, Ignazio; Savoldo, Barbara; Hoyos, Valentina; Weber, Gerrit; Liu, Hao; Kim, Eugene S.; Ittmann, Michael M.; Marchetti, Dario; Dotti, Gianpietro.

In: Nature Medicine, Vol. 21, No. 5, 01.05.2015, p. 524-529.

Research output: Contribution to journalArticle

Caruana, I, Savoldo, B, Hoyos, V, Weber, G, Liu, H, Kim, ES, Ittmann, MM, Marchetti, D & Dotti, G 2015, 'Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes', Nature Medicine, vol. 21, no. 5, pp. 524-529. https://doi.org/10.1038/nm.3833
Caruana, Ignazio ; Savoldo, Barbara ; Hoyos, Valentina ; Weber, Gerrit ; Liu, Hao ; Kim, Eugene S. ; Ittmann, Michael M. ; Marchetti, Dario ; Dotti, Gianpietro. / Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. In: Nature Medicine. 2015 ; Vol. 21, No. 5. pp. 524-529.
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