Cancer cell-intrinsic expression of MHC II in lung cancer cell lines is actively restricted by MEK/ERK signaling and epigenetic mechanisms

Abstract

BackgroundProgrammed 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.MethodsResponsiveness 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.ResultsSingle-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.ConclusionsThese 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.

Single-Cell RNA Sequencing Reveals Tumor Microenvironment Remodeling after Neoadjuvant Immunotherapy in Non-small Cell Lung Cancer

“…Further, CD4+ T cells were activated by CD40-CD40LG and CD28-CD86 interactions in MPR patients. This suggests that although MHC-II expression is usually restricted to APCs, however, MHC-II could also be expressed intrinsically in a subset of cancer cells 83 or induced by IFNγ 29 . Given the low expression of MHC-II in TN patients, it is likely that the expression of MHC-II genes was induced by IFNγ secreted by effector T or NK cells as a result of therapy.…”

“…Given the low expression of MHC-II in TN patients, it is likely that the expression of MHC-II genes was induced by IFNγ secreted by effector T or NK cells as a result of therapy. Recent studies report that inhibition of histone deacetylases (HDAC) and mitogen-activated protein kinase kinase (MEK) enhanced MHC-II expression in NSCLC cell lines 83 . Thus, indicated that promoting antigen presentation via the MHC-II pathway may be a strategy to enhance response to immunotherapy.…”

Targeting KRAS Mutant Non-Small-Cell Lung Cancer: Past, Present and Future

“…It is also notable that responsiveness to PD-1/PD-L1 checkpoint blockage correlates with an interferon gamma-inducible gene signature and major histocompatibility complex class II (MHC II) expression by tumor cells [ 192 ]. Recent data emphasize the active inhibitory role of epigenetic and ERK signaling cascades in restricting cancer cell-intrinsic MHC II expression in NSCLC and suggest their combinatorial inhibition as new responsiveness to checkpoint therapies [ 192 ].…”

Combination Immunotherapies to Overcome Intrinsic Resistance to Checkpoint Blockade in Microsatellite Stable Colorectal Cancer

“…Because most MSS mCRCs are poorly immunogenic, studies have been performed to overcome this limitation by enhancing immunogenicity using various agents. The mitogen-activated protein kinase pathway is known to modulate the expression of major histocompatibility complex class I molecules, thus regulating antigen presentation during carcinogenesis [ 21 , 76 ]. Mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibition enhances major histocompatibility complex class I molecule expression and intratumoral T cell infiltration in preclinical CRC models [ 77 , 78 ].…”