期刊
CANCER IMMUNOLOGY RESEARCH
卷 9, 期 6, 页码 637-650出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-20-080
关键词
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资金
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF)
- Canadian Institutes of Health Research (CIHR)
- Melanoma Research Alliance (MRA)
- Israel Cancer Research Fund (ICRF)
- International Development Research Centre (IDRC)
- Israel Science Foundation (ISF)
- Azrieli Foundation
- Deutsche Forschungsgemeinschaft (DFG)
- Rosetrees Trust
- Perlstein Family Fund
Different splice isoforms of SLAMF6 play different roles in regulating T cell activation and immune responses, with the short isoform SLAMF6(Delta 17-65) having an agonistic effect. Researchers found that by modulating specific splice isoforms of SLAMF6, it is possible to enhance the anti-tumor capacity of tumor-infiltrating lymphocytes, suggesting a potential role in cancer immunotherapy.
SLAMF6 is a homotypic receptor of the Ig-superfamily associated with progenitor-exhausted T cells. Here we show that in humans, SLAMF6 has three splice isoforms involving its V-domain. Although the canonical receptor inhibited T-cell activation through SAP recruitment, the short isoform SLAMF6(Delta 17-65) had a strong agonistic effect. The costimulatory action depended on protein phosphatase SHP1 and led to a cytotoxic molecular profile mediated by the expression of TBX21 and RUNX3. Patients treated with immune checkpoint blockade showed a shift toward SLAMF6(Delta 17-65) in peripheral blood T cells. We developed splice-switching antisense oligonucleotides (ASO) designed to target the relevant SLAMF6 splice junction. Our ASOs enhanced SLAMF6(Delta 17-65) expression in human tumor-infiltrating lymphocytes and improved their capacity to inhibit human melanoma in mice. The yin-yang relationship of SLAMF6 splice isoforms may represent a balancing mechanism that could be exploited to improve cancer immunotherapy.
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