title: ADAP and SKAP55 deficiency suppresses PD-1 expression in CD8+ cytotoxic T lymphocytes for enhanced anti-tumor immunotherapy.
abstract: 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.
authors: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences, Shanghai, China.
authors: Chunyang
authors: C
authors: Li
authors: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences, Shanghai, China.
authors: Weiyun
authors: W
authors: Li
authors: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences, Shanghai, China Shanghai Normal University, Shanghai, China.
authors: Jun
authors: J
authors: Xiao
authors: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences, Shanghai, China.
authors: Shaozhuo
authors: S
authors: Jiao
authors: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences, Shanghai, China.
authors: Fei
authors: F
authors: Teng
authors: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences, Shanghai, China.
authors: Shengjie
authors: S
authors: Xue
authors: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences, Shanghai, China.
authors: Chi
authors: C
authors: Zhang
authors: Shanghai Normal University, Shanghai, China.
authors: Chun
authors: C
authors: Sheng
authors: Institute Pasteur of Shanghai Chinese Academy of Sciences, Shanghai, China.
authors: Qibin
authors: Q
authors: Leng
authors: Cambridge Institute of Medical Research, Cambridge, UK.
authors: Christopher E
authors: CE
authors: Rudd
authors: State Key Laboratory of Virology, Wuhan Institute of Virology Chinese Academy of Sciences, Wuhan, China weibin@wh.iov.cn hongyanwang@sibcb.ac.cn.
authors: Bin
authors: B
authors: Wei
authors: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences, Shanghai, China weibin@wh.iov.cn hongyanwang@sibcb.ac.cn.
authors: Hongyan
authors: H
authors: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D007167:Immunotherapy / Q000379:methods*; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000628:therapy*; D010750:Phosphoproteins / Q000172:deficiency / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; D010750:Phosphoproteins; D061026:Programmed Cell Death 1 Receptor; C491468:Fyb protein, mouse; C491383:Pdcd1 protein, mouse; C514255:SKAP1 protein, mouse
keywords: ADAP/SKAP55; CTL cytotoxicity; CsA; PD‐1; anti‐tumor immunotherapy