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

Abstract

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 (TKIs) on MHC‐I expression in NSCLC cell lines. Appropriate EGFR‐TKIs 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 (PI3K) 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 CD8+ 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.

Role of the dynamic tumor microenvironment in controversies regarding immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations

“…Additionally, several recent studies report that MHC-I and MHC-II expression is downregulated via the IFN-γ signaling pathway and downstream MEK/ERK signaling pathways (Fig. 2) [102,[107][108][109][110][111].…”

“…IFN-γ potentiates the induction of MHC class I (MHCI) and II (MHCII) molecules [102,106]. Watanabe et al found that EGFR-mutant cells have lower levels of human leukocyte antigen (HLA)-B expression than do EGFR-wildtype cells [107] in the presence of IFN-γ. Additionally, several recent studies report that MHC-I and MHC-II expression is downregulated via the IFN-γ signaling pathway and downstream MEK/ERK signaling pathways (Fig.…”

“…To date, preclinical and clinical studies have shown that EGFR-TKIs can induce antitumor immunity through the following [45,79,102,107,108,[153][154][155][156]: potentiating induction of class I (MHCI) and II (MHCII) molecules; promoting Foxp3 degradation to attenuate the inhibitory function of Tregs; reducing the infiltration of Tregs in the TME and inhibiting tumor growth; and enhancing the cytotoxicity of cytotoxic T lymphocytes (CTLs) that mediate antitumor immune response, reduce T cell apoptosis, and increase IFN-γ secretion to enhance the immune system response. Thus, EGFR-TKIs show promising efficacy for anti-PD-1/PD-L1 treatment.…”

MHC Class I Downregulation in Cancer: Underlying Mechanisms and Potential Targets for Cancer Immunotherapy

“…The MEK inhibitors trametinib and cobimetinib have been demonstrated to enhance IRF1 expression and increased STAT1 phosphorylation in human keratinocytes [188]. Watanabe et al [189] reported that treatment of a NSCLC cell line with trametinib also increased MHC-I expression in vitro. Another MEK inhibitor, selumetinib, increased MHC-I expression in papillary thyroid cancer cell lines [2].…”

Combination therapies with mitogen-activated protein kinase kinase inhibitors and immune checkpoint inhibitors in non-small cell lung cancer

“…[ 17 ] Pre-clinical studies demonstrated that acquired resistance of EGFR-TKI could occur through the MEK/ERK pathway by major histocompatibility complex class I molecules down-regulation, which may be reversed by MEKi. [ 18 ] Taken together, when EGFR-TKI failure occurs in EGFR-driven NSCLC patients, we propose that combination of MEKi and immunotherapies can be considered. Further clinical trials are needed.…”