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

Derek A Franklin,Jamaal L James,Margaret L Axelrod,Justin M Balko

doi:10.20517/cdr.2019.109

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, MEKi-induced 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.Conclusion: These findings suggest that MAPK signaling and STAT activation are inversely related in both mouse and human mammary tumors. This work also supports further study of MEKi to increase STAT signaling and potentially, immunotherapy responses through increased MHC-I and PD-L1 expression.

Highlights

Breast cancer is the most commonly diagnosed malignancy in women with 270,000 new cases expected in 2020[1]
These findings suggest that Mitogen activated protein kinase (MAPK) signaling and STAT activation are inversely related in both mouse and human mammary tumors
Reports have shown that activation of the Janus kinases (JAK)/STAT pathway leads to increased expression of PD-L1 and MHC-I[16]

Summary

Introduction

Breast cancer is the most commonly diagnosed malignancy in women with 270,000 new cases expected in 2020[1]. Recent results from the IMpassion130 trial demonstrated increased progression-free survival for patients with > 1% PD-L1 + immune cells within tumors treated with atezolizumab (α-PD-L1) and nab-paclitaxel compared to nabpaclitaxel alone (25 months vs 15.5 months)[6] This data suggests that PD-L1 expression is important for treatment response to atezolizumab and potentially, other ICIs. Previous work from our laboratory has shown that MEK inhibitor (MEKi) treatment increases PD-L1 and MHC-I expression in two breast cancer lines, and that MEKi/PD-L1 combination treatment inhibits tumor growth compared to either single agent treatment in mice[7]. In order to further clarify the relationship between MEKi treatment and PD-L1/ MHC-I expression, we need to first determine whether this relationship is conserved in additional breast cancer models, and second, further examine the mechanism by which MEKi treatment induces immuneassociated protein expression

Objectives

Methods

Results

Conclusion