Cancer Chemotherapy and Pharmacology

, Volume 83, Issue 5, pp 911–920 | Cite as

Disruption of CTLA-4 expression on peripheral blood CD8 + T cell enhances anti-tumor efficacy in bladder cancer

  • Wei Zhang
  • Long Shi
  • Zhilong Zhao
  • Pingping Du
  • Xueshuai Ye
  • Dongbin Li
  • Zhenhua Cai
  • Jinsheng Han
  • Jianhui CaiEmail author
Original Article


Activation of programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) on T cells leads to T cell exhaustion and ultimately facilitates tumor progression. Recent success of using immune cell checkpoint inhibitors offers a great promise to treat various cancers, including bladder cancer. However, the expression pattern and therapeutic value of PD-1 and CTLA-4 in peripheral blood T cells remain largely unexplored. In this study, we presume that disruption of the potential dysregulated checkpoint molecules in peripheral blood T cells may improve the anti-tumor efficacy of cytotoxic T cells in bladder cancer. We showed that both PD-1 and CTLA-4 expression were specifically elevated on CD8 + T cells but not CD4 + T cells in peripheral blood of patients with bladder cancer compared with that in healthy donors. Notably, CTLA-4 expression was significantly higher in muscle-invasive bladder cancer (MIBC) and correlated with tumor size. By blocking CTLA-4 with anti-CTLA-4 antibody and CRISPR-Cas9-mediated CTLA-4 disruption, we revealed that CTLA-4-disrupted CTLs had enhanced cellular immune response and superior cytotoxicity to the CD80/CD86-positive bladder cancer cells in vitro. Moreover, the CTLA-4-disrupted CTLs exhibited a pronounced anti-tumor effect in vivo as demonstrated by prophylactic assay and therapeutic assay in the subcutaneous xenograft model. Collectively, our findings confirm improved therapeutic efficacy of CTLA-4-disrupted CTLs and provides the potential strategy for targeting immune checkpoints to enhance the promising immunotherapy.


Immune checkpoint blockade PD-1 PD-L1 CTLA-4 Bladder cancer 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Graduate school of Hebei Medical UniversityShijiazhuangPeople’s Republic of China
  2. 2.Department of Surgery, Department of Oncology and ImmunotherapyHebei General HospitalShijiazhuangPeople’s Republic of China
  3. 3.Department of SurgeyThe Second Hospital of Hebei Medical UniversityShijiazhuangPeople’s Republic of China
  4. 4.Department of SurgeryThe Third Affiliated Hospital of Jinzhou Medical UniversityJinzhouPeople’s Republic of China
  5. 5.Center of Cell Therapy Engineering TechnologyHebei NOFOY Bio-Tech Co. Ltd.ShijiazhuangPeople’s Republic of China
  6. 6.Department of Gastrointestinal SurgeryThe Second Hospital of Hebei Medical UniversityShijiazhuangPeople’s Republic of China
  7. 7.Handan Central HospitalHandanPeople’s Republic of China
  8. 8.Cangzhou Sino-Western Integrated HospitalCangzhouPeople’s Republic of China

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