ADAP and SKAP55 deficiency suppresses PD‐1 expression in CD8+ cytotoxic T lymphocytes for enhanced anti‐tumor immunotherapy

• 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: ADAP/SKAP55; Adaptor Proteins, Signal Transducing - deficiency; Adaptor Proteins, Signal Transducing - metabolism; Animals; anti‐tumor immunotherapy; CD8-Positive T-Lymphocytes - immunology; CsA; CTL cytotoxicity; EMBO03; EMBO19; Immunotherapy - methods; Membrane Proteins - deficiency; Membrane Proteins - metabolism; Mice; Mice, Knockout; Neoplasms - therapy; PD‐1; Phosphoproteins - deficiency; Phosphoproteins - metabolism; Programmed Cell Death 1 Receptor - metabolism; Research Article; T-Lymphocytes, Cytotoxic - immunology
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201404578

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‐, Ca 2+ ‐, 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. Synopsis ADAP and SKAP55 can enhance PD‐1 expression via the transcription factor NFATc1 in CD8 + CTLs. Targeting this pathway in CTLs enhances cytotoxic responses against tumor cells in vitro and in vivo . ADAP and SKAP55 regulate PD‐1 expression in a Fyn‐, Ca 2+ ‐ and NFATc1‐dependent manner. Deficiency of SKAP55 or ADAP enhances CD8 + CTL cytotoxicity and reduces PD‐1 expression. SKAP55‐ or ADAP‐deficient mice improve efficacy of a DC‐based vaccine for tumor prevention and therapy. Adoptive transfer of SKAP55‐ or ADAP‐deficient CD8 + CTLs significantly blocks tumor growth in wild‐type recipient mice. Graphical Abstract ADAP and SKAP55 can enhance PD‐1 expression via the transcription factor NFATc1 in CD8 + CTLs. Targeting this pathway in CTLs enhances cytotoxic responses against tumor cells in vitro and in vivo .