Targeting TIGIT Inhibits Bladder Cancer Metastasis Through Suppressing IL-32.

Kang Wu,Guoyu Peng,Haoxiang Zheng,Guanghui Zhu,Dongdong Tang,Xulian Shi,Song Wu,Jun Zeng,Yuqing Li,Jiajia Xie

doi:10.3389/fphar.2021.801493

Abstract

Bladder cancer is a highly metastatic tumor and one of the most common malignancies originating in the urinary tract. Despite the efficacy of immune checkpoints, including programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), the effect of immunotherapy for bladder cancer remains unsatisfactory. Therefore, it is urgent to develop new targets to expand immunotherapeutic options. In this study, we utilized single-cell sequencing to explore the cell composition of tumors and detected a subset of Treg cells with high expression of T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) and interleukin (IL)-32. The antitumor immune response was suppressed by this subset of Treg cells, while IL-32 promoted bladder cancer metastasis. Nevertheless, targeting TIGIT not only reversed immunosuppression by restoring the antitumor immune response mediated by T cells but also suppressed the secretion of IL-32 and inhibited the metastasis of bladder cancer cells. Thus, our study provided novel insights into immunosuppression in bladder cancer and highlighted TIGIT as a novel target for immunotherapy of bladder cancer. We also illustrated the mechanism of the dual effect of targeting TIGIT and revealed the metastasis-promoting effect of IL-32 in bladder cancer. Collectively, these findings raise the possibility of utilizing TIGIT as a target against bladder cancer from the bench to the bedside.

Highlights

Treatment strategies for patients with solid tumors have traditionally been based on three different options: surgery, targeted therapies, and cytotoxic therapy (Chauvin and Zarour, 2020)
We found that this subset of Treg cells highly expressed IL-2Rα and forkhead box protein 3 (FOXP3) and TIGIT and IL-32 (Figure 1C)
We examined the expression of TIGIT in Treg cells from murine bladder cancer tissues

Summary

Introduction

Treatment strategies for patients with solid tumors have traditionally been based on three different options: surgery, targeted therapies, and cytotoxic therapy (chemotherapy or radiation therapy) (Chauvin and Zarour, 2020). It is necessary to explore new targets for immunotherapy to facilitate the improved treatment of solid tumors. TIGIT is an immunoreceptor inhibitor checkpoint that has been implicated in tumor immunosurveillance (Manieri et al, 2017; Harjunpaa and Guillerey, 2020). Preclinical models, such as colorectal cancer and melanoma models, have suggested the synergy of anti-TIGIT antibodies with anti-PD-1/PD-L1 antibodies (Curran, 2018). TIGIT molecules have been identified on the surface of CD8+ T cells in bladder cancer, but their function has not been well characterized (Han et al, 2021)

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Conclusion