Repositioning liothyronine for cancer immunotherapy by blocking the interaction of immune checkpoint TIGIT/PVR

Xiuman Zhou,Ling Jiao,Wenjie Zhai,Chunxia Chen,Hongfei Wang,Yanfeng Gao,Xiangrui Cheng,Junhui Chen,Jiangfeng Du,Shanshan Gou,Xiaowen Zhou,Shaomeng Chen,Wenshan Zhao

doi:10.1186/s12964-020-00638-2

Abstract

BackgroundInhibitors targeting immune checkpoint were proved effective in cancer immunotherapy, such as PD-1/PD-L1 blockade. The novel immune checkpoint TIGIT/PVR plays critical roles in suppressing the anti-tumor effects of CD8+ T and NK cells, and dual blockade of TIGIT/PVR and PD-1/PD-L1 by antibody can elicit synergistic effects in tumor models and clinical trials. However, small molecules for TIGIT/PVR blockade have not been investigated.MethodsThe expression of PVR in tumors were analyzed by using TCGA, Oncomine and GEO database, and in cancer cell lines examined by flow cytometry. Natural product compounds were docked to PVR for virtual screening by using the software Molecular Operating Environment (MOE). Candidate compounds were further tested by biolayer interferometry-based binding assay, microscale thermophoresis assay and cell based blocking assay. The in vitro activity of the candidate compound was determined by MTT, peripheral blood mononuclear cells (PBMCs) activation assay and coculture assay. The anti-tumor effects and mechanism were also investigated by using MC38 tumor-bearing mice model and immune cell depletion tumor model.ResultsPVR was over-expressed in many tumor tissues and cancer cell lines, making it a promising therapeutic target. Through virtual screening, binding, and blocking assay, liothyronine was discovered to bind PVR and block the interaction of TIGIT/PVR. Liothyronine could enhance the function of CD4+ and CD8+ T cells in PBMCs. Besides, in the Jurkat-hTIGIT and CHOK1-hPVR coculture assay, liothyronine could reverse the IL-2 secretion inhibition resulted by TIGIT/PVR ligation. Although had no influence on the proliferation of tumor cells in vitro, liothyronine could significantly inhibit tumor growth when administrated in vivo, by enhancing CD8+ T cell infiltration and immune responses in the tumor bearing mice. The immune cell depletion model showed that the anti-tumor effects of liothyronine depends on CD4+ T cells, CD8+ T cells and NK cells.ConclusionsA small molecule liothyronine was discovered to serve as a potential candidate for cancer immunotherapy by blocking the immune checkpoint TIGIT/PVR.-Ev9Py5y6QZb5r8dVDwR9cVideo abstractGraphical abstract

Highlights

Inhibitors targeting immune checkpoint were proved effective in cancer immunotherapy, such as PD1/PD-L1 blockade
The expression analysis of Poliovirus receptor (PVR) in tumor tissues and cell lines To confirm the expression of PVR in tumors, we firstly analyzed the data from The Cancer Genome Atlas (TCGA) using the tools TIMER
PVR expressed in head and neck cancer (HNSC), lung adenocarcinoma (LUAD) and stomach cancer (STAD), which was consistent with the previous study [13, 15, 33]. It expressed across a broad spectrum of cancers including bladder cancer (BLCA), endometrioid cancer (UCEC), esophageal cancer (ESCA), kidney chromophobe (KICH), Kidney papillary cell carcinoma (KIRP), prostate cancer (PRAD), thyroid cancer (THCA), and especially in colon cancer (COAD) and rectal cancer (READ) within 50 datasets

Summary

Introduction

Inhibitors targeting immune checkpoint were proved effective in cancer immunotherapy, such as PD1/PD-L1 blockade. The response rate of PD-1/PD-L1 blockade therapy varies greatly among patients with different types of tumors, which is urgent to be improved [2]. Another treatment dilemma is that adaptive resistance is observed in patients who initially exhibit effective response to PD-1/ PD-L1 antibody [3]. TIGIT was found to be expressed on immune cells (such as CD8+ T and NK cells), and on tumor cells, which making it a potential target for cancer immunotherapy [6]

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Discussion

Conclusion