ADAP and SKAP55 deficiency suppresses PD‐1 expression in CD8+ cytotoxic T lymphocytes for enhanced anti‐tumor immunotherapy
Open accessAbstract
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.
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Concurrent deficiency of ADAP and SKAP55 enhances anti-tumor immunity.
“concurrent deficiency of ADAP and SKAP55 suppresses PD-1 expression in CD8⁺ T cells, thereby enhancing anti-tumor immunity [21].”
From Inhibition of SPI1 by ADAP Regulates S100A8/A9 Signaling in Macrophages to Control the Development of Colitis (2026) · cites this paper as [21]
Concurrent deficiency of ADAP and SKAP55 suppresses PD-1 expression in CD8+ T cells.
“concurrent deficiency of ADAP and SKAP55 suppresses PD-1 expression in CD8⁺ T cells, thereby enhancing anti-tumor immunity [21].”
From Inhibition of SPI1 by ADAP Regulates S100A8/A9 Signaling in Macrophages to Control the Development of Colitis (2026) · cites this paper as [21]
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References 64 · Cited by 60
- Authors
- Li, C., Li, W., Xiao, J., Jiao, S., Teng, F., Xue, S., Zhang, C., Sheng, C., Leng, Q., Rudd, C. E., Wei, B., & Wang, H.
- Affiliations
- Chinese Academy of Sciences (CN)
- Shanghai Normal University (CN)
- University of Cambridge (GB)
- Corresponding author
- Wei, Bin
- Wang, Hongyan
- ORCID
- Venue
- EMBO Molecular Medicine
- Published
- 2015-04-07
- Volume
- 7
- Issue
- 6
- Pages
- 754-769
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC4459816
- OpenAlex
- W2161596417
- Cited by
- 60
- References
- 64
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 10 · 2023: 9 · 2022: 2 · 2021: 6 · 2020: 6 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 8 · 2015: 4
- FWCI
- 2.33
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Ministry of Science and Technology of China (2012CB910800)
- National Natural Science Foundation of China (31422018, 31070778, 31370859, 31300723)
- Shanghai Pujiang program (11PJ1410700)
- WIV “One‐Three‐Five” Strategic Programs
- Hundred Talents Program of the Chinese Academy of Sciences
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- ADAP, PD-1 expression, CD8+ cytotoxic T lymphocytes, anti-tumor immunotherapy, NFATc1, Fyn, calcium signaling, CTL cytotoxicity, DC vaccine, metastasis, CTLA-4, regulatory T cells, cyclosporine, adoptive T cell therapy
- MeSH terms
- Animals, Immunotherapy, Membrane Proteins, Neoplasms, Phosphoproteins, T-Lymphocytes, Cytotoxic, Mice, Knockout, CD8-Positive T-Lymphocytes, Adaptor Proteins, Signal Transducing, Mice, Programmed Cell Death 1 Receptor
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