Cancer cell-intrinsic expression of MHC II in lung cancer cell lines is actively restricted by MEK/ERK signaling and epigenetic mechanisms
Open Access
- 20 December 2019
- journal article
- research article
- Published by BMJ in Journal for ImmunoTherapy of Cancer
- Vol. 8 (1), e000441
- https://doi.org/10.1136/jitc-2019-000441
Abstract
Background Programmed death 1/programmed death ligand 1 (PD-1/PD-L1) targeted immunotherapy affords clinical benefit in ~20% of unselected patients with lung cancer. The factor(s) that determine whether a tumor responds or fails to respond to immunotherapy remains an active area of investigation. We have previously defined divergent responsiveness of two KRAS-mutant cell lines to PD-1/PD-L1 blockade using an orthotopic, immunocompetent mouse model. Responsiveness to PD-1/PD-L1 checkpoint blockade correlates with an interferon gamma (IFNγ)-inducible gene signature and major histocompatibility complex class II (MHC II) expression by cancer cells. In the current study, we aim to identify therapeutic targets that can be manipulated in order to enhance cancer-cell-specific MHC II expression. Methods Responsiveness to IFNγ and induction of MHC II expression was assessed after various treatment conditions in mouse and human non-small cell lung cancer (NSCLC) cell lines using mass cytometric and flow cytometric analysis. Results Single-cell analysis using mass and flow cytometry demonstrated that IFNγ consistently induced PD-L1 and MHC class I (MHC I) across multiple murine and human NSCLC cell lines. In contrast, MHC II showed highly variable induction following IFNγ treatment both between lines and within lines. In mouse models of NSCLC, MHC II induction was inversely correlated with basal levels of phosphorylated extracellular signal-regulated kinase (ERK) 1/2, suggesting potential mitogen-activated protein (MAP) kinase-dependent antagonism of MHC II expression. To test this, cell lines were subjected to varying levels of stimulation with IFNγ, and assessed for MHC II expression in the presence or absence of mitogen-activated protein kinase kinase (MEK) inhibitors. IFNγ treatment in the presence of MEK inhibitors significantly enhanced MHC II induction across multiple lung cancer lines, with minimal impact on expression of either PD-L1 or MHC I. Inhibition of histone deacetylases (HDACs) also enhanced MHC II expression to a more modest extent. Combined MEK and HDAC inhibition led to greater MHC II expression than either treatment alone. Conclusions These studies emphasize the active inhibitory role that epigenetic and ERK signaling cascades have in restricting cancer cell-intrinsic MHC II expression in NSCLC, and suggest that combinatorial blockade of these pathways may engender new responsiveness to checkpoint therapies.Funding Information
- National Cancer Institute (P30 CA046934, P50 CA058187, R01 CA162226, R01 CA236222)
- LUNGevity Foundation
- U.S. Department of Veterans Affairs (IK2BX001282)
- Cancer League of Colorado
- Golfers Against Cancer
This publication has 52 references indexed in Scilit:
- Histone deacetylase inhibitors activate CIITA and MHC class II antigen expression in diffuse large B‐cell lymphomaImmunology, 2013
- Mechanisms of Resistance to Crizotinib in Patients with ALK Gene Rearranged Non–Small Cell Lung CancerClinical Cancer Research, 2012
- Expression Regulation of Major Histocompatibility Complex Class I and Class II Encoding GenesFrontiers in Immunology, 2011
- MHC class II regulation by epigenetic agents and microRNAsImmunologic Research, 2009
- Depletion of Cytosolic Phospholipase A2 in Bone Marrow–Derived Macrophages Protects against Lung Cancer Progression and MetastasisCancer Research, 2009
- Expression of CIITA-related MHCII molecules in tumors linked to prognosis in hepatocellular carcinomaInternational Journal of Oncology, 2009
- Fluorescent cell barcoding in flow cytometry allows high-throughput drug screening and signaling profilingNature Methods, 2006
- IL-6-STAT3 Controls Intracellular MHC Class II αβ Dimer Level through Cathepsin S Activity in Dendritic CellsImmunity, 2005
- Histone acetylation regulates the cell type specific CIITA promoters, MHC class II expression and antigen presentation in tumor cellsInternational Immunology, 2005
- Histone Deacetylase 1/mSin3A Disrupts Gamma Interferon-Induced CIITA Function and Major Histocompatibility Complex Class II Enhanceosome FormationMolecular and Cellular Biology, 2003