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

Pule, M.A. et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat. Med. 14, 1264–1270 (2008).

Kershaw, M.H. et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin. Cancer Res. 12, 6106–6115 (2006).

Bawley, V.S. et al. T cells redirected against HER2 for adoptive immunotherapy for HER2-positive osteosarcoma. Cancer Res. 72, 3500 (2012).

Kalos, M. et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 3, 95ra73 (2011).

Brentjens, R.J. et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl. Med. 5, 177ra38 (2013).

Zou, W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat. Rev. Cancer 5, 263–274 (2005).

Savoldo, B. et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J. Clin. Invest. 121, 1822–1826 (2011).

Muller, W.A. Leukocyte-endothelial-cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol. 24, 327–334 (2003).

Parish, C.R. The role of heparan sulphate in inflammation. Nat. Rev. Immunol. 6, 633–643 (2006).

Yadav, R., Larbi, K.Y., Young, R.E. & Nourshargh, S. Migration of leukocytes through the vessel wall and beyond. Thromb. Haemost. 90, 598–606 (2003).

Bernfield, M. et al. Functions of cell surface heparan sulfate proteoglycans. Annu. Rev. Biochem. 68, 729–777 (1999).

de Mestre, A.M., Staykova, M.A., Hornby, J.R., Willenborg, D.O. & Hulett, M.D. Expression of the heparan sulfate-degrading enzyme heparanase is induced in infiltrating CD4+ T cells in experimental autoimmune encephalomyelitis and regulated at the level of transcription by early growth response gene 1. J. Leukoc. Biol. 82, 1289–1300 (2007).

Vlodavsky, I., Ilan, N., Naggi, A. & Casu, B. Heparanase: structure, biological functions, and inhibition by heparin-derived mimetics of heparan sulfate. Curr. Pharm. Des. 13, 2057–2073 (2007).

Yurchenco, P.D. & Schittny, J.C. Molecular architecture of basement membranes. FASEB J. 4, 1577–1590 (1990).

Fridman, R. et al. Soluble antigen induces T lymphocytes to secrete an endoglycosidase that degrades the heparan sulfate moiety of subendothelial extracellular matrix. J. Cell. Physiol. 130, 85–92 (1987).

Naparstek, Y., Cohen, I.R., Fuks, Z. & Vlodavsky, I. Activated T lymphocytes produce a matrix-degrading heparan sulphate endoglycosidase. Nature 310, 241–244 (1984).

Vlodavsky, I. et al. Expression of heparanase by platelets and circulating cells of the immune system: possible involvement in diapedesis and extravasation. Invasion Metastasis 12, 112–127 (1992).

Bartlett, M.R., Underwood, P.A. & Parish, C.R. Comparative analysis of the ability of leucocytes, endothelial cells and platelets to degrade the subendothelial basement membrane: evidence for cytokine dependence and detection of a novel sulfatase. Immunol. Cell Biol. 73, 113–124 (1995).

Smith, C.A. et al. Production of genetically modified Epstein-Barr virus-specific cytotoxic T cells for adoptive transfer to patients at high risk of EBV-associated lymphoproliferative disease. J. Hematother. 4, 73–79 (1995).

Baraz, L., Haupt, Y., Elkin, M., Peretz, T. & Vlodavsky, I. Tumor suppressor p53 regulates heparanase gene expression. Oncogene 25, 3939–3947 (2006).

Mondal, A.M. et al. p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes. J. Clin. Invest. 123, 5247–5257 (2013).

Gallagher, J.T. Heparan sulfate: growth control with a restricted sequence menu. J. Clin. Invest. 108, 357–361 (2001).

Iozzo, R.V. Matrix proteoglycans: from molecular design to cellular function. Annu. Rev. Biochem. 67, 609–652 (1998).

Nakajima, M., Irimura, T., Di, F.N. & Nicolson, G.L. Metastatic melanoma cell heparanase. Characterization of heparan sulfate degradation fragments produced by B16 melanoma endoglucuronidase. J. Biol. Chem. 259, 2283–2290 (1984).

Craddock, J.A. et al. Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J. Immunother. 33, 780–788 (2010).

Patterson, D.M., Shohet, J.M. & Kim, E.S. Preclinical models of pediatric solid tumors (neuroblastoma) and their use in drug discovery. Curr. Protoc. Pharmacol. 52, 14.17.1–14.17.18 (2011).

Geldres, C. et al. T lymphocytes redirected against the chondroitin sulfate proteoglycan-4 control the growth of multiple solid tumors both in vitro and in vivo. Clin. Cancer Res. 20, 962–971 (2014).

Arvatz, G., Barash, U., Nativ, O., Ilan, N. & Vlodavsky, I. Post-transcriptional regulation of heparanase gene expression by a 3′ AU-rich element. FASEB J. 24, 4969–4976 (2010).

Lu, W.C., Liu, Y.N., Kang, B.B. & Chen, J.H. Trans-activation of heparanase promoter by ETS transcription factors. Oncogene 22, 919–923 (2003).

Wilson, T.J. & Singh, R.K. Proteases as modulators of tumor-stromal interaction: primary tumors to bone metastases. Biochim. Biophys. Acta 1785, 85–95 (2008).

Yvon, E. et al. Immunotherapy of metastatic melanoma using genetically engineered GD2-specific T cells. Clin. Cancer Res. 15, 5852–5860 (2009).

Roy, M. et al. Antisense-mediated suppression of Heparanase gene inhibits melanoma cell invasion. Neoplasia 7, 253–262 (2005).

Zhang, L., Sullivan, P., Suyama, J. & Marchetti, D. Epidermal growth factor-induced heparanase nucleolar localization augments DNA topoisomerase I activity in brain metastatic breast cancer. Mol. Cancer Res. 8, 278–290 (2010).

Pulè, M.A. et al. A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells. Mol. Ther. 12, 933–941 (2005).

Vera, J. et al. T lymphocytes redirected against the kappa light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells. Blood 108, 3890–3897 (2006).

Naggi, A. et al. Modulation of the heparanase-inhibiting activity of heparin through selective desulfation, graded N-acetylation, and glycol splitting. J. Biol. Chem. 280, 12103–12113 (2005).

Zhang, L., Ngo, J.A., Wetzel, M.D. & Marchetti, D. Heparanase mediates a novel mechanism in lapatinib-resistant brain metastatic breast cancer. Neoplasia 17, 101–113 (2015).