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Published on: June 12, 2021
Blocking TIGIT/CD155 signalling reverses CD8+ T cell exhaustion and enhances the antitumor activity in cervical
Lu Liu1,2,3, Aihong Wang4, Xiaoli Liu1,2,3
1Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Address: No.107, west culture road, Jinan, 250012, Shandong, China.
Objective:
TIGIT/CD155 has attracted widespread attention as a new immune checkpoint and a potential target for cancer immunotherapy. In our study, we evaluated the role of TIGIT/CD155 checkpoints in the progression of cervical cancer.
Methods:
The expression of CD155 and TIGIT in cervical cancer tissues was detected using flow cytometry, immunohistochemistry (IHC) and gene expression profiling. In vivo and in vitro experiments have proven that blocking TIGIT/CD155 restores the ability of CD8+ T cells to produce cytokines. Changes in the NF-κB and ERK pathways were detected using western blotting (WB) after blocking TIGIT/CD155 signalling.
Results:
TIGIT expression was elevated in patients with cervical cancer. High TIGIT expression in CD8+ T lymphocytes from patients with cervical cancer promotes the exhaustion of CD8+ T lymphocytes. In addition, CD155 is expressed at high levels in cervical cancer tissues and is negatively correlated with the level of infiltrating CD8+ T cells. We found that TIGIT, upon binding to CD155 and being phosphorylated, inhibited NF-κB and ERK activation by recruiting SHIP-1, resulting in the downregulation of cytokine production. Blocking TIGIT in activated CD8+ T cells attenuates the inhibitory effect of SHIP-1 on CD8+ T cells and enhances the activation of NF-κB and ERK. In vivo and in vitro experiments have proven that blocking TIGIT/CD155 restores the ability of CD8+ T cells to produce cytokines. Injecting the blocking antibody TIGIT in vivo inhibits tumour growth and enhances CD8+ T lymphocyte function. Treatment with a combination of TIGIT and PD-1 inhibitors further increases the efficacy of the TIGIT blocking antibody.
Conclusions:
Our research shows that TIGIT/CD155 is a potential therapeutic target for cervical cancer.
Insights
The TIGIT/CD155 immune checkpoint is elevated in cervical cancer, promoting T cell exhaustion. Blocking this pathway restores T cell function and inhibits tumor growth, offering a new therapeutic target.
Area of Science:
- Immunology
- Oncology
- Cancer Immunotherapy
Background:
- TIGIT/CD155 represents a novel immune checkpoint with significant potential in cancer immunotherapy.
- Understanding the role of TIGIT/CD155 in cervical cancer progression is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role and impact of the TIGIT/CD155 immune checkpoint pathway in the development and progression of cervical cancer.
- To evaluate the therapeutic potential of targeting TIGIT/CD155 in cervical cancer models.
Main Methods:
- Flow cytometry, immunohistochemistry, and gene expression profiling were used to assess CD155 and TIGIT expression in cervical cancer tissues.
- In vitro and in vivo experiments were conducted to analyze the effects of TIGIT/CD155 blockade on CD8+ T cell function and signaling pathways (NF-κB, ERK).
- Western blotting was employed to detect changes in the NF-κB and ERK pathways following TIGIT/CD155 signaling blockade.
Main Results:
- Elevated TIGIT expression was observed in cervical cancer patients, correlating with CD8+ T cell exhaustion.
- High CD155 levels in cervical cancer tissues showed a negative correlation with CD8+ T cell infiltration.
- TIGIT/CD155 signaling, via SHIP-1 recruitment, inhibits NF-κB and ERK activation, suppressing cytokine production; blockade restores T cell function and inhibits tumor growth.
- Combination therapy with TIGIT and PD-1 inhibitors demonstrated enhanced efficacy.
Conclusions:
- The TIGIT/CD155 pathway plays a significant role in cervical cancer progression by inhibiting anti-tumor immunity.
- Targeting TIGIT/CD155 presents a promising therapeutic strategy for cervical cancer immunotherapy.
- Blocking TIGIT/CD155 can restore CD8+ T cell activity and suppress tumor growth, suggesting its potential as a standalone or combination therapy.
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