期刊
CELLULAR & MOLECULAR IMMUNOLOGY
卷 19, 期 10, 页码 1153-1167出版社
CHIN SOCIETY IMMUNOLOGY
DOI: 10.1038/s41423-022-00911-z
关键词
Sphingosine kinase; Programmed cell death ligand 1; Programmed cell death protein 1; Melanoma; Tumor microenvironment; Immune checkpoint blockade
类别
资金
- National Key Research and Development Program of China [2019YFA0111600, 2019YFE0120800]
- Natural Science Foundation of China for Outstanding Young Scholars [82022060]
- National Natural Science Foundation of China [81874242, 31800979, 62102455]
- Natural Science Foundation of Hunan Province for Outstanding Young Scholars [2019JJ30040]
- China Postdoctoral Science Foundation [2020M682587]
- Hunan Outstanding Postdoctoral Innovative Talents Program [2021RC2035]
This study reveals the important role of SPHK1 in tumor immunity and shows that its inhibition can suppress tumor growth and promote antitumor immunity. Additionally, SPHK1 and MTA3 are identified as biological markers for predicting the efficacy of anti-PD-1 mAb therapy in melanoma patients.
Immune checkpoint blockade (ICB) exhibits considerable benefits in malignancies, but its overall response rate is limited. Previous studies have shown that sphingosine kinases (SPHKs) are critical in the tumor microenvironment (TME), but their role in immunotherapy is unclear. We performed integrative analyses including bioinformatics analysis, functional study, and clinical validation to investigate the role of SPHK1 in tumor immunity. Functionally, we demonstrated that the inhibition of SPHK1 significantly suppressed tumor growth by promoting antitumor immunity in immunocompetent melanoma mouse models and tumor T-cell cocultures. A mechanistic analysis revealed that MTA3 functions as the downstream target of SPHK1 in transcriptionally regulating tumor PD-L1. Preclinically, we found that anti-PD-1 monoclonal antibody (mAb) treatment significantly rescued tumor SPHK1 overexpression or tumor MTA3 overexpression-mediated immune evasion. Significantly, we identified SPHK1 and MTA3 as biological markers for predicting the efficacy of anti-PD-1 mAb therapy in melanoma patients. Our findings revealed a novel role for SPHK1 in tumor evasion mediated by regulating the MTA3-PD-L1 axis, identified SPHK1 and MTA3 as predictors for assessing the efficacy of PD-1 mAb treatment, and provided a therapeutic possibility for the treatment of melanoma patients.
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