ADAP and SKAP 55 deficiency suppresses PD ‐1 expression in CD 8 + cytotoxic T lymphocytes for enhanced anti‐tumor immunotherapy

PD‐1 negatively regulates CD8+ cytotoxic T lymphocytes (CTL) cytotoxicity and anti‐tumor immunity. However, it is not fully understood how PD‐1 expression on CD8+ CTL is regulated during anti‐tumor immunotherapy. In this study, we have identified that the ADAP‐SKAP55 signaling module reduced CD8+ CT...

Full description

Saved in:
Bibliographic Details
Published in:EMBO molecular medicine 2015-06, Vol.7 (6), p.754-769
Main Authors: Li, Chunyang, Li, Weiyun, Xiao, Jun, Jiao, Shaozhuo, Teng, Fei, Xue, Shengjie, Zhang, Chi, Sheng, Chun, Leng, Qibin, Rudd, Christopher E, Wei, Bin, Wang, Hongyan
Format: Article
Language:English
Subjects:
Adoptive transfer
Antigens
Apoptosis
Calcium
CD4 antigen
CD8 antigen
Cell adhesion & migration
Cytotoxicity
Effector cells
Experiments
Foxp3 protein
Fyn protein
Immunotherapy
Kinases
Lymphocytes
Lymphocytes T
Metastases
Phosphorylation
Prevention
Proteins
Studies
Transcription factors
Tumors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:PD‐1 negatively regulates CD8+ cytotoxic T lymphocytes (CTL) cytotoxicity and anti‐tumor immunity. However, it is not fully understood how PD‐1 expression on CD8+ CTL is regulated during anti‐tumor immunotherapy. In this study, we have identified that the ADAP‐SKAP55 signaling module reduced CD8+ CTL cytotoxicity and enhanced PD‐1 expression in a Fyn‐, Ca2+‐, and NFATc1‐dependent manner. In DC vaccine‐based tumor prevention and therapeutic models, knockout of SKAP55 or ADAP showed a heightened protection from tumor formation or metastases in mice and reduced PD‐1 expression in CD8+ effector cells. Interestingly, CTLA‐4 levels and the percentages of tumor infiltrating CD4+Foxp3+ Tregs remained unchanged. Furthermore, adoptive transfer of SKAP55‐deficient or ADAP‐deficient CD8+ CTLs significantly blocked tumor growth and increased anti‐tumor immunity. Pretreatment of wild‐type CD8+ CTLs with the NFATc1 inhibitor CsA could also downregulate PD‐1 expression and enhance anti‐tumor therapeutic efficacy. Together, we propose that targeting the unrecognized ADAP‐SKAP55‐NFATc1‐PD‐1 pathway might increase efficacy of anti‐tumor immunotherapy.
ISSN:1757-4676
1757-4684
DOI:10.15252/emmm.201404578