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

Nat Med. 2015 May;21(5):524-9. doi: 10.1038/nm.3833. Epub 2015 Apr 13.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement
  • Cell Separation
  • Cells, Cultured
  • Enzyme-Linked Immunosorbent Assay
  • Extracellular Matrix / chemistry
  • Female
  • Flow Cytometry
  • Glucuronidase / physiology*
  • Heparin / analogs & derivatives
  • Heparin / chemistry
  • Humans
  • MCF-7 Cells
  • Male
  • Mice
  • Neoplasm Invasiveness
  • Neoplasm Transplantation
  • Promoter Regions, Genetic
  • Proteoglycans / chemistry
  • RNA, Messenger / metabolism
  • Receptors, Antigen, T-Cell / genetics*
  • T-Lymphocytes / immunology*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Proteoglycans
  • RNA, Messenger
  • Receptors, Antigen, T-Cell
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • heparin proteoglycan
  • Heparin
  • heparanase
  • Glucuronidase