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

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.