Abstract 982: Hyaluronan (HA) depletion increases tumor accessibility of T cell and therapeutic PD-L1 monoclonal antibody in HAhigh tumors
Authors: Netai C. Singha, Chunmei Zhao, Jesse Bahn, Adrian Radi, H. Michael Shepard, Zhongdong Huang
Journal: Cancer Research (2015)

Abstract Tumor initiation and progression is a complex interaction between host and tumor. One of the essential elements for tumor progression is evasion of the host immune system. Among the mechanisms important for host immune cell evasion is the amplification of receptor tyrosine kinases, and tumor secretion of immune suppressive cytokines, like TGF-β, suppression of activated T cells by various intrinsic immune response regulatory mechanisms 1-3. Additionally, tumor cells evolve to express cell-associated programmed death 1 (PD1) ligands (PD-L1 or LD-L2), which promotes tumor cell growth by inactivating PD1 expressing activated T cells 3-4. Recent reports suggest a role of the tumor microenvironment (TME) as an immunosuppressive environment by accumulating hyaluronan (HA)5-7, which then results in accumulation of water and resulting high interstitial fluid pressure and sequelae, including blood vessel compression, and decreased perfusion8-10. Hyaluronan depletion from solid tumors with high levels of HA (HAhigh) reverses these physiological effects, resulting in increased chemotherapeutic drug penetration and tumor growth inhibition in preclinical animal models 8-10. In this report we investigated whether increasing the access of therapeutic immune checkpoint monoclonal antibodies and effector T cells into the HAhigh tumor can enhance activated T cell-mediated tumor cell lysis. We have generated human hyaluronan synthase and PD-L1 overexpressing tumor cell lines to study (i) the role of HA in PD-1 and PD-L1 interaction in HAhigh tumor cells, and (ii) whether HA depletion increases the efficacy of tumor cell killing by PD-1 positive cytotoxic T lymphocytes in the presence of PD-L1 blocking monoclonal antibody. Our data show that HAhigh tumor cells form an HA-rich barrier that restricts T cell access to tumor cell and HA depletion by PEGPH20, a pegylated PH20, allowed T cells to access tumor cell. HA depletion increases HAhigh PD-L1 positive tumor cells killing by activated T cell in the presence of anti-human PD-L1 monoclonal antibody (MAb). Furthermore, HA depletion by PEGPH20 increased the access of T cell and anti-human PD-L1 MAb in HAhigh xenograft tumors, suggesting that PEGPH20 may enhance efficacy of immune check point blocking therapeutic PD-L1 MAb in HAhigh tumors. References: 1. Rabinovich et al. Annu Rev Immunol., 2007;25:267-96. 2. Hudzika et al. Cell Growth Differ. 1990; 1:129-34. 3. Quezada et al. British Journal of Cancer, 2013; 108: 1560-1565. 4. Zou et al. Nature Reviews Immunology, 2008; 8: 467-477. 5. Sironen et al. Exp Cell Res 2011;317:383-91. 6. Kultti et al. Cancers 2012;4:873-903. 7. Tlsty et al. Annu Rev Pathol 2006;1:119-50. 8. Thompson et al. Mol Cancer Ther 2010;9:3052-64. 9. Jacobetz et al. Gut 2013;62:112-20. 10. Provenzano et al. Cancer Cell 2012;21:418-29. Citation Format: Netai C. Singha, Chunmei Zhao, Jesse Bahn, Adrian Radi, H. Michael Shepard, Zhongdong Huang. Hyaluronan (HA) depletion increases tumor accessibility of T cell and therapeutic PD-L1 monoclonal antibody in HAhigh tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 982. doi:10.1158/1538-7445.AM2015-982