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The efficacy of programmed cell death–1 ( PD ‐1) blockade in patients with non–small cell lung cancer ( NSCLC ) positive for epidermal growth factor receptor ( EGFR ) gene mutations has been found to be limited, but the underlying mechanisms for this poor response have remained obscure. Given that the recognition by T cells of tumor antigens presented by major histocompatibility complex class I ( MHC ‐I) molecules is essential for an antitumor immune response, we examined the effects of  EGFR  tyrosine kinase inhibitors ( TKI s) on  MHC ‐I expression in  NSCLC  cell lines. Appropriate  EGFR ‐ TKI s increased  MHC ‐I expression at the  mRNA  and cell surface protein levels in  NSCLC  cells positive for   EGFR   mutations including those with the T790M secondary mutation. Trametinib, an inhibitor of the extracellular signal–regulated kinase ( ERK ) kinase  MEK , also increased  MHC ‐I expression, whereas the phosphatidylinositol 3‐kinase ( PI 3K) inhibitor buparlisib did not, suggesting that the  MEK ‐ ERK  pathway mediates the down‐regulation of  MHC ‐I expression in response to  EGFR  activation. Immunohistochemical analysis of   EGFR  ‐mutated  NSCLC  specimens obtained before and after  EGFR ‐ TKI  treatment also revealed down‐regulation of phosphorylated forms of  EGFR  and  ERK  in association with up‐regulation of  MHC ‐I, an increased number of infiltrating  CD 8 +  T cells, and increased  PD ‐1 ligand 1 expression after such treatment. Our results thus suggest that mutational activation of  EGFR  inhibits  MHC ‐I expression through the  MEK ‐ ERK  pathway in  NSCLC  and thereby contributes to the poor response of such tumors to immunotherapy. Further studies are warranted to evaluate the relation between  EGFR ‐ MEK ‐ ERK  signaling in and the immune response to   EGFR  ‐mutated  NSCLC . 

cancer science

Mutational activation of the epidermal growth factor receptor down‐regulates major histocompatibility complex class I expression via the extracellular signal‐regulated kinase in non–small cell lung cancer