| First Author | Li C | Year | 2015 |
| Journal | EMBO Mol Med | Volume | 7 |
| Issue | 6 | Pages | 754-69 |
| PubMed ID | 25851535 | Mgi Jnum | J:233407 |
| Mgi Id | MGI:5784599 | Doi | 10.15252/emmm.201404578 |
| Citation | Li C, et al. (2015) ADAP and SKAP55 deficiency suppresses PD-1 expression in CD8+ cytotoxic T lymphocytes for enhanced anti-tumor immunotherapy. EMBO Mol Med 7(6):754-69 |
| abstractText | 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. |
