Anti-tumor immunotherapy aims to prevent or treat tumors by boost immunity. CD8+ cytotoxic T lymphocytes (CTLs) play major role during cancer immune surveillance, which could infiltrate into tumor to kill tumor cells effectively. However, tumor environment induces expression of a negative receptor PD-1 (Programmed Cell Death Receptor 1) on CD8+ CTLs, which blocks cytotoxicity. Therapies targeting PD-1 has shown promising results to enhance anti-tumor efficacy in clinical patients, and the US Food and Drug Administration (FDA) approved anti-PD-1 antibodies for the treatment of melanoma this January. However, it is still not fully understood which intracellular molecules in CD8+ CTLs could be targeted to block PD-1 upregulation, thus enhancing anti-tumor immunity.
A research group led by WANG Hongyan from the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences identified that immune adaptors SKAP55 (src kinaseassociated protein of 55 kDa) and ADAP (adhesion and degranulation promoting adaptor protein) enhance the expression and activation of the transcription factor NFATc1 to promote PD-1 expression in CD8+ CTLs. Blocking NFATc1 activity and deficiency of ADAP or SKAP55 in CTLs decrease PD-1 expression and enhance cytotoxicity. Using three in vivo anti-tumor immunotherapy methods, including DC vaccine-induced prevention and therapeutic models as well as adoptive CD8+ CTL transfer model, researchers found that SKAP55- or ADAP-deficient mice protect from tumor formation with the reduced PD-1 expression in CD8+ CTLs.
This study provides a novel mechanism of tumor antigen-induced PD-1 expression in CD8+ CTLs, and suggests that targeting the unrecognized ADAP-SKAP55-NFATc1-PD-1 pathway enhances anti-tumor immunity. This work entitled “ADAP and SKAP55 deficiency suppresses PD-1 expression in CD8+ cytotoxic T lymphocytes for enhanced anti-tumor immunotherapy” was published online in EMBO Molecular Medicine on April 7, 2015.
This study was done in collaboration with Dr. WEI Bin from Wuhan Institute of Virology. This work was financially supported by grants from the Ministry of Science and Technology of China, the National Natural Science Foundation of China, the Program of the Chinese Academy of Sciences, the WIV “One-Three-Five” Strategic Programs, and the Shanghai Pujiang Program.
AUTHOR CONTACT:
WANG Hongyan, Principal Investigator
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,
Shanghai, China
Phone: 021-54921086
E-mail: hongyanwang@sibcb.ac.cn
Fig. Left, Model showing that the ADAP-SKAP55 module regulates PD-1 expression via Fyn-, Ca2+- and NFATc1-dependent manner. Right, SKAP55 deficient mice enhance DC-based vaccine for tumor immunotherapy in vivo (Image by Prof. Wang Hongyan’s group).
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