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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  JAK 2/ STAT 1 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.

cancer science

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