title: Inhibition of mitogen-activated protein kinase pathway can induce upregulation of human leukocyte antigen class I without PD-L1-upregulation in contrast to interferon-γ treatment.
abstract: 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-γ (IFN-γ). 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-γ. 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-γ; there was an additive effect in the upregulation of HLA class I when treated with the combination of MAPK inhibitors and IFN-γ, and there was no overlapping activation of JAK2/STAT1 and Erk1/2 molecules when treated with either IFN-γ or MAPK inhibitors. Furthermore, we showed that IFN-γ-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.
authors.affiliation: Department of Surgery, National University of Singapore, Singapore City, Singapore.
authors.forename: Kousaku
authors.initials: K
authors.lastname: Mimura
authors.forename: Ley-Fang
authors.initials: LF
authors.lastname: Kua
authors.forename: Kensuke
authors.initials: K
authors.lastname: Shiraishi
authors.forename: Lim
authors.initials: L
authors.lastname: Kee Siang
authors.forename: Asim
authors.initials: A
authors.lastname: Shabbir
authors.forename: Mayumi
authors.initials: M
authors.lastname: Komachi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakano
authors.forename: Wei-Peng
authors.initials: WP
authors.lastname: Yong
authors.forename: Jimmy
authors.initials: J
authors.lastname: So
authors.forename: Koji
authors.initials: K
authors.lastname: Kono
mesh_terms: D060890:B7-H1 Antigen / Q000032:analysis / Q000502:physiology*; D045744:Cell Line, Tumor; D005419:Flavonoids / Q000494:pharmacology; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D015854:Up-Regulation
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D005419:Flavonoids; D015395:Histocompatibility Antigens Class I; D007371:Interferon-gamma; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: Cytotoxic T lymphocyte; PD-L1; human leukocyte antigen-A; interferon-γ; mitogen-activated protein kinase