Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti–PD-1 response in NSCLC

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

doi:10.26508/lsa.201900328

Cited by 39 publications

(28 citation statements)

References 39 publications

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“…The sensitivity of tumor cells to IFN-γ can play a critical role in the response to PD-1/PD-L1 blockade, which was demonstrated on lung cancer cell lines [48]. However, our data provide evidence that deactivated IFN-γ signaling may not be sufficient for PD-L1 and MHC-I reduction on tumor cells and resistance to PD-L1 blockade.…”

Section: Discussionmentioning

confidence: 57%

Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade

Vackova

Piatakova

Poláková

et al. 2020

IJMS

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Programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) blockade is a promising therapy for various cancer types, but most patients are still resistant. Therefore, a larger number of predictive biomarkers is necessary. In this study, we assessed whether a loss-of-function mutation of the interferon (IFN)-γ receptor 1 (IFNGR1) in tumor cells can interfere with anti-PD-L1 therapy. For this purpose, we used the mouse oncogenic TC-1 cell line expressing PD-L1 and major histocompatibility complex class I (MHC-I) molecules and its TC-1/A9 clone with reversibly downregulated PD-L1 and MHC-I expression. Using the CRISPR/Cas9 system, we generated cells with deactivated IFNGR1 (TC-1/dIfngr1 and TC-1/A9/dIfngr1). In tumors, IFNGR1 deactivation did not lead to PD-L1 or MHC-I reduction on tumor cells. From potential inducers, mainly IFN-α and IFN-β enhanced PD-L1 and MHC-I expression on TC-1/dIfngr1 and TC-1/A9/dIfngr1 cells in vitro. Neutralization of the IFN-α/IFN-β receptor confirmed the effect of these cytokines in vivo. Combined immunotherapy with PD-L1 blockade and DNA vaccination showed that IFNGR1 deactivation did not reduce tumor sensitivity to anti-PD-L1. Thus, the impairment of IFN-γ signaling may not be sufficient for PD-L1 and MHC-I reduction on tumor cells and resistance to PD-L1 blockade, and thus should not be used as a single predictive marker for anti-PD-1/PD-L1 cancer therapy.

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Section: Discussionmentioning

confidence: 57%

Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade

Vackova

Piatakova

Poláková

et al. 2020

IJMS

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“…We previously reported that the CMT167 and LLC mouse models of NSCLC differ in their response to PD-1-targeted immunotherapy, with divergent IFNγ signatures in vivo. 31 To further examine this, we assessed the ability of these cells to respond to in vitro IFNγ stimulation, measuring protein expression at the single-cell level. CMT167 and LLC cells were cultured under either basal or IFNγ stimulated conditions and subjected to mass cytometry, with cellular phenotypes characterized using the PhenoGraph clustering algorithm, visualized using the tSNE dimensionality reduction approach.…”

Section: Resultsmentioning

confidence: 99%

“…The relative message levels of each target gene were normalized to GAPDH. 31 20 All statistical analyzes were done using GraphPad Prism software. Specific statistical tests performed are described in figure legends, with statistical significance defined if p<0.05.…”

Section: Quantitative Real-time-pcrmentioning

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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“…Ayers et al have developed a gene signature involving responsiveness to interferon gamma (IFNγ) associate with response (Ayers et al, 2017). Our lab has demonstrated that at least in mouse models of lung cancer responsiveness to IFNγ is a determinant of response to anti-PD-1 therapy (Bullock et al, 2019).…”

Section: Regulators Of Tumor Immunitymentioning

confidence: 99%

Eicosanoids in Cancer: New Roles in Immunoregulation

2020

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Eicosanoids represent a family of active biolipids derived from arachidonic acid primarily through the action of cytosolic phospholipase A2-α. Three major downstream pathways have been defined: the cyclooxygenase (COX) pathway which produces prostaglandins and thromboxanes; the 5-lipoxygenase pathway (5-LO), which produces leukotrienes, lipoxins and hydroxyeicosatetraenoic acids, and the cytochrome P450 pathway which produces epoxygenated fatty acids. In general, these lipid mediators are released and act in an autocrine or paracrine fashion through binding to cell surface receptors. The pattern of eicosanoid production is cell specific, and is determined by cell-specific expression of downstream synthases. Increased eicosanoid production is associated with inflammation and a panel of specific inhibitors have been developed designated non-steroidal anti-inflammatory drugs. In cancer, eicosanoids are produced both by tumor cells as well as cells of the tumor microenvironment. Earlier studies demonstrated that prostaglandin E2, produced through the action of COX-2, promoted cancer cell proliferation and metastasis in multiple cancers. This resulted in the development of COX-2 inhibitors as potential therapeutic agents. However, cardiac toxicities associated with these agents limited their use as therapeutic agents. The advent of immunotherapy, especially the use of immune checkpoint inhibitors has revolutionized cancer treatment in multiple malignancies. However, the majority of patients do not respond to these agents as monotherapy, leading to intense investigation of other pathways mediating immunosuppression in order to develop rational combination therapies. Recent data have indicated that PGE2 has immunosuppressive activity, leading to renewed interest in targeting this pathway. However, little is known regarding the role of other eicosanoids in modulating the tumor microenvironment, and regulating anti-tumor immunity. This article reviews the role of eicosanoids in cancer, with a focus on their role in modulating the tumor microenvironment. While the role of PGE2 will be discussed, data implicating other eicosanoids, especially products produced through the lipoxygenase and cytochrome P450 pathway will be examined. The existence of small molecular inhibitors and activators of eicosanoid pathways such as specific receptor blockers make them attractive candidates for therapeutic trials, especially in combination with novel immunotherapies such as immune checkpoint inhibitors.

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Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti–PD-1 response in NSCLC

Cited by 39 publications

References 39 publications

Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade

Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade

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

Eicosanoids in Cancer: New Roles in Immunoregulation

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