ADAP and SKAP55 deficiency suppresses PD-1 expression in CD8+ cytotoxic T
lymphocytes for enhanced anti-tumor immunotherapy
#MMPMID25851535
Li C
; Li W
; Xiao J
; Jiao S
; Teng F
; Xue S
; Zhang C
; Sheng C
; Leng Q
; Rudd CE
; Wei B
; Wang H
EMBO Mol Med
2015[Jun]; 7
(6
): 754-69
PMID25851535
show ga
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.
|Adaptor Proteins, Signal Transducing/deficiency/*metabolism
[MESH]
|Animals
[MESH]
|CD8-Positive T-Lymphocytes/*immunology
[MESH]
|Immunotherapy/*methods
[MESH]
|Membrane Proteins/deficiency/*metabolism
[MESH]
|Mice
[MESH]
|Mice, Knockout
[MESH]
|Neoplasms/*therapy
[MESH]
|Phosphoproteins/deficiency/*metabolism
[MESH]
|Programmed Cell Death 1 Receptor/*metabolism
[MESH]
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