当前位置： SCI文献检索 > CANCER CHEMOTHERAPY AND PHARMACOLOGY期刊下所有文献 > Disruption of CTLA-4 expression on peripheral blood CD8 + T cell enhances anti-tumor efficacy in bladder cancer.

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

Abstract：

: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.

journal_name

Cancer Chemother Pharmacol

journal_title

Cancer chemotherapy and pharmacology

authors

Zhang W,Shi L,Zhao Z,Du P,Ye X,Li D,Cai Z,Han J,Cai J

doi

10.1007/s00280-019-03800-x

subject

Has Abstract

pub_date

2019-05-01 00:00:00

pages

911-920

issue

5

eissn

0344-5704

issn

1432-0843

pii

10.1007/s00280-019-03800-x

journal_volume

83

pub_type

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