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Targeting TIGIT Inhibits Bladder Cancer Metastasis Through Suppressing IL-32

Authors
  • Wu, Kang1, 2, 3
  • Zeng, Jun4
  • Shi, Xulian1, 3
  • Xie, Jiajia1, 3
  • Li, Yuqing1, 2, 3
  • Zheng, Haoxiang1, 3
  • Peng, Guoyu1, 3
  • Zhu, Guanghui1, 3
  • Tang, Dongdong1, 3
  • Wu, Song1, 5, 6, 7
  • 1 The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen , (China)
  • 2 Chinese Academy of Sciences, Guangzhou , (China)
  • 3 Shenzhen Following Precision Medicine Research Institute, Shenzhen , (China)
  • 4 Chongqing Normal University, Chongqing , (China)
  • 5 Medical Laboratory of Shenzhen Luohu People’s Hospital, Shenzhen , (China)
  • 6 Shantou University Medical College, Shantou , (China)
  • 7 The First Affiliated Hospital of Guangzhou Medical University, Guangzhou , (China)
Type
Published Article
Journal
Frontiers in Pharmacology
Publisher
Frontiers Media SA
Publication Date
Jan 05, 2022
Volume
12
Identifiers
DOI: 10.3389/fphar.2021.801493
Source
Frontiers
Keywords
Disciplines
  • Pharmacology
  • Original Research
License
Green

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.

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