MEK inhibition activates STAT signaling to increase breast cancer immunogenicity via MHC-I expression

Abstract

Aim: Immunotherapy and immune checkpoint inhibitors (ICI) have changed cancer care for many patients; however, breast cancers have exhibited minimal response to single agent ICI therapy. There is a significant need to identify novel targets capable of increasing cancer cell immunogenicity and response to ICIs in breast cancer. Mitogen activated protein kinase (MAPK) signaling is essential for many cellular processes but the relationship between MAPK signaling and cancer cell immunogenicity is less well understood. Recent reports suggest that MEK inhibition (MEKi) affects the tumor-immune microenvironment by altering the expression of interferon responsive PD-L1 and MHC-I through unknown mechanisms. Methods: Using western blotting and flow cytometry, we sought to determine whether MEKi affects JAK-STAT signaling upstream of PD-L1 and MHC-I expression in a panel of mouse mammary cancer and triple negative breast cancer cell lines. Results: The cell lines tested exhibited increased STAT activation in response to MEKi treatment. Furthermore, MEKi-induced MHC-I and PD-L1 expression are dependent upon STAT1 in MMTV-Neu cells. Interestingly, MEKiinduced STAT activation and interferon-responsive protein expression are abrogated with ErbB-family inhibitor co-treatment in MMTV-Neu cells, suggesting ErbB receptor signaling dependence, but not in basal-like cell lines. Importantly, analysis of basal-like breast cancer patient samples exhibited an inverse relationship between STAT1 and Ras/MAPK activation signatures.

Tyrosine Kinase Inhibitors Stimulate HLA Class I Expression by Augmenting the IFNγ/STAT1 Signaling in Hepatocellular Carcinoma Cells

“…Using the selective MEK inhibitor trametinib and PI3K inhibitor buparlisib, we revealed that inhibition of the MEK/ERK pathway, but not of the PI3K/AKT pathway, enhanced STAT1 activation and subsequent expression of cell surface HLA-I and B2M molecules in HCC cell lines. Consistent with our in vitro findings, trametinib has been reported to activate STAT1 and subsequent HLA-I induction in many other types of cancers ( 24 , 37 , 38 ). Notably, ERK has been identified as a transcriptional repressor of IFNγ response genes including STAT1 ( 39 ).…”

“…Consistent with our in vitro findings, trametinib has been reported to activate STAT1 and subsequent HLA-I induction in many other types of cancers (24,37,38). Notably, ERK has been identified as a transcriptional repressor of IFNg response genes including STAT1 (39).…”

Mechanisms of MHC-I Downregulation and Role in Immunotherapy Response

“…Numerous oncogenic pathways have been reported to affect the expression of MHC-I and related antigen presentation components, including the MAPK and EGFR pathways ( 100 , 101 ). The MAPK pathway is thought to negatively influence MHC-I expression through decreased IRF and STAT1 expression resulting in reduced levels of tumor infiltrating lymphocytes ( 100 , 102 , 103 ). MEK inhibitors (MEKi), cobimetinib and trametinib, have been shown to enhance IRF1 expression and increased phosphorylation of STAT1 in human epidermal models ( 104 ).…”

Breast Cancer Tumor Microenvironment and Molecular Aberrations Hijack Tumoricidal Immunity

“…Therefore, the dual MEK plus PD-L1/PD-1 inhibition synergized antitumor immune responses [ 186 ]. In another independent study, Franklin et al found MEK inhibition not only affects the tumor-immune microenvironment by altering the expression of interferon-inducible MHC-I and PD-Ll expression, but also enhances immunogenicity and improves susceptibility to immune checkpoint blockade therapy [ 187 ].…”