Hepatocellular Carcinoma Cells Up-regulate PVRL1, Stabilizing PVR and Inhibiting the Cytotoxic T-Cell Response via TIGIT to Mediate Tumor Resistance to PD1 Inhibitors in Mice

Abstract

BACKGROUND & AIMS: Immune checkpoint inhibitors are effective in the treatment of some hepatocellular carcinomas (HCCs), but these tumors do not always respond to inhibitors of programmed cell death 1 (PDCD1, also called PD1). We investigated mechanisms of resistance of liver tumors in mice to infiltrating T cells. METHODS: Mice were given hydrodynamic tail vein injections of clustered regularly interspaced short palindromic repeats-Cas9 (CRISPR-Cas9) and transposon vectors to disrupt Trp53 and overexpress C-Myc (Trp53 KO /C-Myc OE mice). Pvrl1 and Pvrl3 were knocked down in Hepa1-6 cells by using short hairpin RNAs. Hepa1-6 cells were injected into livers of C57BL/6 mice; some mice were given intraperitoneal injections of antibodies against PD1, T-cell immunoreceptor with Ig and ITIM domains (TIGIT), or CD8 before the cancer cells were injected. Liver tissues were collected from mice and analyzed by histology, immunohistochemistry, and quantitative real-time polymerase chain reaction; tumors were analyzed by mass cytometry using markers

Cancer Immunotherapy and the Nectin Family

“…TIGIT antagonism is expected to reverse coinhibitory signaling downstream of TIGIT ( Johnston et al 2014;Liu et al 2012Liu et al , 2013Lozano et al 2012) and indirectly enhance costimulatory signaling downstream of DNAM-1 (Fourcade et al 2018, Jin et al 2020, Johnston et al 2014, Lozano et al 2012. Preclinically, TIGIT-blocking antibodies have demonstrated activity in multiple mouse models and on effector T cells, NK cells, and regulatory T cells (Dixon et al 2018, Chauvin et al 2020, Guillerey et al 2018, Hung et al 2018, Johnston et al 2014, Chiu et al 2020, Minnie et al 2018, Waight et al 2018. Similar effects have also been reported in several in vitro assays with human lymphocytes (Chauvin et al 2015, Chew et al 2016, Fourcade et al 2018, Inozume et al 2016, Jin et al 2020, Johnston et al 2014, Waight et al 2018.…”

Identification METTL18 as a Potential Prognosis Biomarker and Associated With Immune Infiltrates in Hepatocellular Carcinoma

“…In addition, cytotoxic cells, also known as CD8 + T lymphocytes with cytotoxic granules, are the important anti-tumor effector cells ( 46 ). One research has reported that hepatocellular carcinoma cells could mediate the progression, development and tumor resistance to PD1 by inhibiting the cytotoxic T cell response ( 47 ). Therefore, our results reveal the potent modulating role of METTL18 in immune response with liver cancer.…”

Immunmodulatory Treatment Strategies of Hepatocellular Carcinoma: From Checkpoint Inhibitors Now to an Integrated Approach in the Future

“…TIGIT was found to be upregulated in patients with advanced fibrosis [97] and in chronic viral hepatitis leading to HCC [98]. In preclinical HCC models, TIGIT contributed to immunosuppressive effects and potentially resistance to PD-1 treatment [99,100]. In clinical samples, TIGIT expression increased with tumor dedifferentiation and with higher AFP expression [101].…”