Enhancing Efficacy of the PD-1/PD-L1 Inhibitor-Mediated Anti-Liver Cancer Immunotherapy Through Promoting CD8+ T-Cell Infiltration by Targeting Angiopoietin-1
Abstract
This proposal plans to develop a novel way to enhance therapeutic efficacy of the immune checkpoint inhibitors against liver cancer (a Fiscal Year 2015 Peer Reviewed Cancer Research Program PRCRP Topic Area) and addresses the militarily relevant risk factors such as infectious agents associated with liver cancer and gaps in liver cancer treatment and survivorship that affect the general population as well as military members and veterans (Military Relevance Focus Areas). Hepatocellular carcinoma (HCC) accounts for ~90% of all liver cancers and is a major cause of cancer-related death worldwide. The major cause of HCC is chronic hepatitis and cirrhosis that lead to chronic hepatocyte damage due to Hepatitis B and C Virus (HBV and HCV) infection and chronic alcohol abuse. Military personnel have an increased chance of virus infection during deployment and combat and are in higher risk of developing liver cancer. Treatment options for HCC patients are limited and the HCC prognosis remains poor. The reality urges for development of more efficacious, less toxic, longer-lasting, and targeted novel therapies to achieve better clinical outcomes and significantly improved life quality for HCC patients. To achieve that, we must first identify the key signaling pathways/components that are responsible for the disease manifestations and identify novel therapeutic targets/agents/combinations to combat for this disease. Several signaling pathways including the Hippo signaling pathway have been implicated in the hepatic carcinogenesis and the HCC progression. The Hippo signaling pathway controls organ size, proliferation, apoptosis, tissue regeneration, and tumorigenesis and YAP and TAZ are two key downstream effectors of the Hippo pathway. Higher YAP and TAZ levels/activities have been correlated to the cancer growth/progression and worse prognosis. YAP and TAZ act as oncogenes in several cancer types including HCC. The pro-tumor effects of YAP/TAZ are exerted through their target genes. We show that TAZ knockdown (KD) reduces whereas expression of a constitutively active (CA) TAZ upregulates expression of angiopoietin-1 (Angpt1), suggesting that Angpt1 is a potential novel target gene of the TAZ containing transcription complex. Angpt1, a ligand of Tie-2 receptor tyrosine kinase (RTK) that is highly expressed by endothelial cells (ECs), promotes vascular integrity and attenuates inflammation by reducing lymphocyte adhesion to ECs and trans-endothelial migration. Angpt1 is amplified in ~19% HCCs. We show that HCC cells express high levels of Angpt1 and that increased Angpt1 expression inhibits CD8+ T cell infiltration into mouse hepatoma, suggesting a potential novel role of Angpt1 in regulating anti-tumor immune response because the tumor-infiltrating T cells are required for anti-tumor immunity. Cancer evades host immune system attack by inhibiting T cell activation through the interaction of the immune checkpoint proteins such as PD-1 and its ligands PD-L1/2. Immune checkpoint inhibitors are being developed against a variety of cancers and have shown promises. We show that anti-mouse PD-1 antibody inhibited mouse hepatoma growth in vivo, suggesting potential utility of the checkpoint blockade in the HCC treatment. Little is known about the molecular determinants that govern the cancer resistance to the checkpoint blockade. Identifying and targeting these determinants are the keys to enhance therapeutic efficacy of the checkpoint inhibitors. We hypothesize that Angpt1 is a key downstream target gene of the Hippo pathway and that high Angpt1 levels predict the reduced HCC response to the checkpoint inhibitors and Angpt1 inhibits the HCC response to the checkpoint blockade by blocking CD8+ T cell infiltration into HCCs whereas Angpt1 inhibition promotes CD8+T cell infiltration and increases efficacy of anti-PD-1/PD-L1/2 therapy. We further hypothesize that simultaneous inhibition of Angpt1 and PD-1/PD-L1 together w
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610280
Entities
People
- Qin Yu
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army