title: Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes.
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.
authors: Center for Cell and Gene Therapy, Baylor College of Medicine and Houston Methodist Hospital, Houston, Texas, USA.
authors: Ignazio
authors: I
authors: Caruana
authors: 1] Center for Cell and Gene Therapy, Baylor College of Medicine and Houston Methodist Hospital, Houston, Texas, USA. [2] Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
authors: Barbara
authors: B
authors: Savoldo
authors: Center for Cell and Gene Therapy, Baylor College of Medicine and Houston Methodist Hospital, Houston, Texas, USA.
authors: Valentina
authors: V
authors: Hoyos
authors: Center for Cell and Gene Therapy, Baylor College of Medicine and Houston Methodist Hospital, Houston, Texas, USA.
authors: Gerrit
authors: G
authors: Weber
authors: Biostatistics Shared Resource, Baylor College of Medicine, Houston, Texas, USA.
authors: Hao
authors: H
authors: Liu
authors: Department of Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
authors: Eugene S
authors: ES
authors: Kim
authors: 1] Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA. [2] Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, USA. [3] Michael E. DeBakey Department of Veterans Affairs Medical Center, Dan L. Duncan Cancer Center, Houston, Texas, USA.
authors: Michael M
authors: MM
authors: Ittmann
authors: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA.
authors: Dario
authors: D
authors: Marchetti
authors: 1] Center for Cell and Gene Therapy, Baylor College of Medicine and Houston Methodist Hospital, Houston, Texas, USA. [2] Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA. [3] Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors: Gianpietro
authors: G
authors: Dotti
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D002469:Cell Separation; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000737:chemistry; D005260:Female; D005434:Flow Cytometry; D005966:Glucuronidase / Q000502:physiology*; D006493:Heparin / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D011509:Proteoglycans / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D006493:Heparin; D011509:Proteoglycans; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D016159:Tumor Suppressor Protein p53; D000099175:Heparanase; C495901:TP53 protein, human; C036090:heparin proteoglycan