Cancer Cell–Intrinsic Expression of MHC Class II Regulates the Immune Microenvironment and Response to Anti–PD-1 Therapy in Lung Adenocarcinoma

Johnson, Amber M.; Bullock, Bonnie; Neuwelt, Alexander J.; Poczobutt, Joanna M.; Kaspar, Rachael E.; Li, Howard; Kwak, Jeff; Hopp, Katharina; Weiser-Evans, Mary C.; Heasley, Lynn E.; Schenk, Erin L.; Clambey, Eric T.; Nemenoff, Raphael A.

doi:10.4049/jimmunol.1900778

Cited by 93 publications

(95 citation statements)

References 51 publications

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“…Indeed, tumor specific MHC-II expression is associated with superior prognosis and/or improved response to immune checkpoint inhibitor therapy in multiple cancers, as well as enhanced tumor rejection in mouse models 27 , 28 , 59 – 62 . Recent loss of function and complementation studies in murine carcinoma cells also showed that tumor cell expression of MHC-II is associated with higher Th1 cytokine levels, T-cell infiltration, and sensitivity to anti-PD-1 therapy 63 .…”

Section: Discussionmentioning

confidence: 99%

High MHC-II expression in Epstein–Barr virus-associated gastric cancers suggests that tumor cells serve an important role in antigen presentation

Ghasemi

Tessier

Gameiro

et al. 2020

Sci Rep

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EBV-associated gastric adenocarcinomas (EBVaGCs) often exhibit better clinical outcomes than EBV negative gastric cancers (GCs), which could be related to their consistent expression of foreign viral antigens. Antigen-presenting cells (APCs) present peptide antigens in the context of the class-II major histocompatibility complex (MHC-II). During inflammatory conditions, epithelial cells express MHC-II and function as accessory APCs. Utilizing RNA-seq data from nearly 400 GC patients, we determined the impact of EBV-status on expression of MHC-II components, genes involved in their regulation, and T-cell co-stimulation. Virtually all MHC-II genes were significantly upregulated in EBVaGCs compared to normal tissues, or other GC subtypes. Genes involved in antigen presentation were also significantly upregulated in EBVaGCs, as were the key MHC-II transcriptional regulators CIITA and RFX5. This was unexpected as the EBV encoded BZLF1 protein can repress CIITA transcription and is expressed in many EBVaGCs. Furthermore, MHC-II upregulation was strongly correlated with elevated intratumoral levels of interferon-gamma. In addition, expression of co-stimulatory molecules involved in T-cell activation and survival was also significantly increased in EBVaGCs. Thus, gastric adenocarcinoma cells may functionally contribute to the highly immunogenic tumor microenvironment observed in EBVaGCs via a previously unappreciated role in interferon-induced antigen presentation.

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Section: Discussionmentioning

confidence: 99%

High MHC-II expression in Epstein–Barr virus-associated gastric cancers suggests that tumor cells serve an important role in antigen presentation

Ghasemi

Tessier

Gameiro

et al. 2020

Sci Rep

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“…An important recent observation was made by Johnson and colleagues concerning the participation of MHC-II expression in anti-PD-1 therapies [ 143 ]. Two orthotopic immunocompetent murine models of non-small cell lung cancer, the cell line CMT167, which is sensitive to anti-PD1 therapy and the Lewis lung carcinoma (LLC), which is resistant, were used.…”

Section: Ciita and Cancermentioning

confidence: 99%

“…Ectopic expression of CIITA in LLC rendered these cells MHC-II-positive and sensitized the tumors to anti-PD-1 therapy. Upregulation of CIITA was also associated with increased T-cell infiltration and a survival benefit in patient-derived lung adenocarcinomas [ 143 ].…”

Section: Ciita and Cancermentioning

confidence: 99%

The MHC Class II Transactivator CIITA: Not (Quite) the Odd-One-Out Anymore among NLR Proteins

Machado

Steimle

2021

IJMS

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In this review, we discuss the major histocompatibility complex (MHC) class II transactivator (CIITA), which is the master regulator of MHC class II gene expression. CIITA is the founding member of the mammalian nucleotide-binding and leucine-rich-repeat (NLR) protein family but stood apart for a long time as the only transcriptional regulator. More recently, it was found that its closest homolog, NLRC5 (NLR protein caspase activation and recruitment domain (CARD)-containing 5), is a regulator of MHC-I gene expression. Both act as non-DNA-binding activators through multiple protein–protein interactions with an MHC enhanceosome complex that binds cooperatively to a highly conserved combinatorial cis-acting module. Thus, the regulation of MHC-II expression is regulated largely through the differential expression of CIITA. In addition to the well-defined role of CIITA in MHC-II GENE regulation, we will discuss several other aspects of CIITA functions, such as its role in cancer, its role as a viral restriction element contributing to intrinsic immunity, and lastly, its very recently discovered role as an inhibitor of Ebola and SARS-Cov-2 virus replication. We will briefly touch upon the recently discovered role of NLRP3 as a transcriptional regulator, which suggests that transcriptional regulation is, after all, not such an unusual feature for NLR proteins.

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“…Notably, while both CMT167 and LLC cells show induction of some IFNγ-inducible genes in vivo, including PD-L1, CMT167 cells showed a unique induction of genes encoding the MHC class II antigen presentation and processing pathway. 12 In this study, we aimed to characterize the determinants of divergent IFNγ responsiveness between these tumor lines in vitro in order to gain mechanistic insights that may lead to novel approaches to enhance IFNγ sensitivity and thus make more tumors susceptible to PD-1/ PD-L1 checkpoint blockade, with an emphasis on MHC II regulation. Our studies point to a critical requirement for epigenetic and post-translational-dependent mechanisms that actively restrict IFNγ induction of the MHC class II machinery in NSCLC.…”

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confidence: 99%

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

Neuwelt

Kimball

Johnson

et al. 2020

J Immunother Cancer

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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.

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Cancer Cell–Intrinsic Expression of MHC Class II Regulates the Immune Microenvironment and Response to Anti–PD-1 Therapy in Lung Adenocarcinoma

Cited by 93 publications

References 51 publications

High MHC-II expression in Epstein–Barr virus-associated gastric cancers suggests that tumor cells serve an important role in antigen presentation

High MHC-II expression in Epstein–Barr virus-associated gastric cancers suggests that tumor cells serve an important role in antigen presentation

The MHC Class II Transactivator CIITA: Not (Quite) the Odd-One-Out Anymore among NLR Proteins

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

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