期刊
CANCER SCIENCE
卷 105, 期 10, 页码 1236-1244出版社
WILEY
DOI: 10.1111/cas.12503
关键词
Cytotoxic T lymphocyte; human leukocyte antigen-A; interferon-; mitogen-activated protein kinase; PD-L1
类别
资金
- Clinician Scientist Award (CSA) from the National Medical Research Council of Singapore
- Clinician Scientist-Individual Research Grant (CS-IGR) from the National Medical Research Council of Singapore
- Grants-in-Aid for Scientific Research [24591833] Funding Source: KAKEN
Recently, we reported that human leukocyte antigen (HLA) class I expression is predominantly regulated by the mitogen-activated protein kinase (MAPK) pathway as one of the oncogenic regulations of HLA class I expression. In the present study, we examined mechanisms of how HLA class I and PD-L1 are regulated by MAPK inhibitors and interferon- (IFN-). Furthermore, we evaluated the expression of major signal transduction molecules by Western blot and anti-tumor CTL activity by a cytotoxic assay when HLA class I and PD-L1 were modulated by MAPK inhibitors and/or IFN-. As a result, we confirmed, as a more general phenomenon, that the inhibition of MAPK could upregulate HLA class I expression in a panel of human solid tumors (n=26). Of note, we showed that MAPK inhibitors act on the upregulation of HLA class I expression through a different pathway from IFN-; there was an additive effect in the upregulation of HLA class I when treated with the combination of MAPK inhibitors and IFN-, and there was no overlapping activation of JAK2/STAT1 and Erk1/2 molecules when treated with either IFN- or MAPK inhibitors. Furthermore, we showed that IFN--treatment impaired the tumor-specific CTL activity due to the upregulation of PD-L1 in spite of the upregulation of HLA class I, while MAPK inhibitors can augment the tumor-specific CTL activity due to the upregulated HLA class I without PD-L1 alterations. In conclusion, in addition to the original anti-proliferative activity, MAPK inhibitors may work toward the enhancement of T-cell-mediated anti-tumor immunity through the upregulation of HLA class I without the upregulation of PD-L1.
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