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

By Ignazio Caruana, B. Savoldo, V. Hoyos, G. Weber, Hao Liu, Eugene S. Kim, M. Ittmann, D. Marchetti, G. Dotti. Nature Medicine, 2015

739 citations recorded by the source corpus.

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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/5c6f71a8a14ab8ce94ce9f349634f8af0d6e4b16

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In Immunology

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Citations in the corpus

• Engineering strategies to overcome the current roadblocks in CAR T cell therapy (2019, result): “Anti-GD2 CAR T cells engineered to degrade heparin sulfate proteo-glycans in the ECM through expression of hepari-nase had an improved capacity to infiltrate xenograft tumours in mice and prolonged survival as compared with CAR T cells lacking heparinase expression 151 .”
• Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments (2023, background): “Thus, reengineered CAR-T cell with overexpression of heparinase, which can degrade ECM components and increases T-cell infiltration, strikingly inhibits tumor growth [604].”