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Single-cell profiling of tumor infiltrating T cells and macrophages [Nanostring]

ABSTRACT: Effective therapies for non-small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with potential to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. Herein we evaluated the immunoregulatory properties of histone deacetylase (HDAC) and bromodomain inhibitors, two classes of drugs that modulate the epigenome, with a focus on key cell subsets that are engaged in an immune response. By evaluating human peripheral blood and NSCLC tumors, we show that the selective HDAC6 inhibitor ricolinostat promotes phenotypic changes that support enhanced T cell activation and improved function of antigen presenting cells. The bromodomain inhibitor JQ1 attenuated CD4+Foxp3+ T regulatory cell suppressive function and synergized with ricolinostat to facilitate immune-mediated tumor growth arrest, leading to prolonged survival of mice with lung adenocarcinomas. Collectively, our findings highlight the immunomodulatory effects of two epigenetic modifiers that, together, promote T cell-mediated anti-tumor immunity and demonstrate their therapeutic potential for treatment of NSCLC. 6 Kras-mutant/p53-deficient lung tumors T cells and macrophages were analyzed wth Nanostring mouse PanCancer immune module

ORGANISM(S): Mus musculus

PROVIDER: GSE98044 | GEO | 2017/04/22

SECONDARY ACCESSION(S): PRJNA383804

REPOSITORIES: GEO

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Single-cell profiling of tumor infiltrating T cells and macrophages [RNA-Seq]

Project description:Effective therapies for non-small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with potential to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. Herein we evaluated the immunoregulatory properties of histone deacetylase (HDAC) and bromodomain inhibitors, two classes of drugs that modulate the epigenome, with a focus on key cell subsets that are engaged in an immune response. By evaluating human peripheral blood and NSCLC tumors, we show that the selective HDAC6 inhibitor ricolinostat promotes phenotypic changes that support enhanced T cell activation and improved function of antigen presenting cells. The bromodomain inhibitor JQ1 attenuated CD4+Foxp3+ T regulatory cell suppressive function and synergized with ricolinostat to facilitate immune-mediated tumor growth arrest, leading to prolonged survival of mice with lung adenocarcinomas. Collectively, our findings highlight the immunomodulatory effects of two epigenetic modifiers that, together, promote T cell-mediated anti-tumor immunity and demonstrate their therapeutic potential for treatment of NSCLC.

2017-04-22 | GSE98048 | GEO

Non-canonical splicing junctions between exons and transposable elements represent a source of immunogenic recurrent neo-antigens in cancer patients

Project description:ost characterized tumor antigens are ‘genomic’, i.e. encoded by canonical, non-canonical or somatically mutated genomic sequences. We investigate here the presentation and immunogenicity of tumor antigens derived from non-canonical mRNA splicing events between coding exons and transposable elements (TEs). Comparing non-small cell lung cancer (NSCLC), an immunogenic tumor type, and diverse non-tumor tissues, we identify several thousand splicing junctions between exons and diverse TE classes. A subset of these junctions is both tumor-specific and shared across patients. HLA-I peptidomic identifies peptides encoded by tumor-specific junctions in primary NSCLC samples and lung tumor cell lines. Recurrent junction-encoded peptides are immunogenic in vitro and CD8+ T cells specific for junction-encoded epitopes are present in tumors and tumor-draining lymph nodes from NSCLC patients. We conclude that non-canonical splicing junctions between exons and TEs represent a source of recurrent, immunogenic tumor-specific antigens in NSCLC cancer patients.

2023-02-27 | PXD034820 | Pride

TGFÎ² confers resistance to radiotherapy in non-small cell lung cancer

Project description:Radiotherapy is standard of care for inoperable non-small cell lung cancers (NSCLC) but adenocarcinoma NSCLC respond more poorly than squamous cell NSCLC. Transforming growth factor Î² (TGFÎ²) activity is induced by radiation and plays a recently recognized role in the DNA damage response. Here we show in murine lung tumor model that radiation activates TGFÎ² acutely and persistently and that TGFÎ² neutralizing antibody, 1D11, systemic treatment increased tumor control following either fractionated or single high dose radiation regimes. TGFÎ² dependent genes in the irradiated tumor indicated crosstalk between innate and adaptive immunity but therapeutic benefit of 1D11 in irradiated tumors in immunocompromised mice suggested that innate immune cells are more influential than the adaptive immune response. Irradiated tumors in which TGFÎ² was blocked were highly hypoxic, exhibit pronounced microvascular damage and promoted neither cancer-associated fibroblasts nor recruit bone marrow derived cells (BMDC). Tumor educated immature BMDC were significant sources of TGFÎ² and inhibiting BMDC recruitment achieved tumor growth control in response to RT comparable to TGFÎ² inhibition. Thus, radiation-induced TGFÎ² both compromises tumor control by RT and promotes reestablishment of the tumor microenvironment. Concordant with the critical role of TGFÎ² activity in RT, radiation resistant NSCLC adenocarcinomas exhibit higher TGFÎ² activity compared to squamous cell NSCLC, which suggests a rationale for using TGFÎ² inhibition to augment radiotherapy. Lewis lung cancer (LLC) model were established in 6 to 8 week-old C57BL/6 female mice by subcutaneous injection. When tumors were 60-80 mm3, Mice were randomized to achieve comparable mean tumor size for each treatment group as indicated below. Tumor growth were monitored and tumors were collected and characterized by gene expression profiling and immunostaining.

2015-12-15 | E-GEOD-73095 | biostudies-arrayexpress

Therapeutic efficacy of BET bromodomain protein inhhibitor and PD-1 blockade in genetically engineered mouse model of non-small cell lung cancer

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2018-08-14 | GSE114601 | GEO

Expression profiling of lung adenocarcinoma TPC tumor cells in Kras-driven NSCLC mouse model

Project description:Sustained tumor progression has been attributed to a distinct population of tumor-propagating cells (TPCs). To identify TPCs relevant to lung cancer pathogenesis, we investigated functional heterogeneity in tumor cells isolated from Kras-driven mouse models of non-small cell lung cancer (NSCLC). CD24+ITGB4+Notchhi cells are capable of propagating tumor growth in both a clonogenic and an orthotopic serial transplantation assay. While all four Notch receptors mark TPCs, Notch3 plays a non-redundant role in tumor cell propagation in two mouse model and in human NSCLC. The TPC population is enriched after chemotherapy and the gene signature of mouse TPCs correlates with poor prognosis in human NSCLC. The unique role of Notch3 in tumor propagation may provide a therapeutic target for NSCLC Primary lung adenocarcinoma tumor cells were FACS sorted based on expression of CD24, ITGB4 and Notch. TPC cells are defined by Cd24+ITGB4+ Notch(high), and the remainder tumor cells are non-TPC cells. Samples were derived from six mice.

2013-07-08 | E-GEOD-46439 | biostudies-arrayexpress

Expression profiling of CD24+ and CD24- tumor cells in Kras-driven NSCLC mouse model

Project description:Sustained tumor progression has been attributed to a distinct population of tumor-propagating cells (TPCs). To identify TPCs relevant to lung cancer pathogenesis, we investigated functional heterogeneity in tumor cells isolated from Kras-driven mouse models of non-small cell lung cancer (NSCLC). CD24+ITGB4+Notchhi cells are capable of propagating tumor growth in both a clonogenic and an orthotopic serial transplantation assay. While all four Notch receptors mark TPCs, Notch3 plays a non-redundant role in tumor cell propagation in two mouse model and in human NSCLC. The TPC population is enriched after chemotherapy and the gene signature of mouse TPCs correlates with poor prognosis in human NSCLC. The unique role of Notch3 in tumor propagation may provide a therapeutic target for NSCLC Highly purified primary tumor cells were FACS sorted based on expression of CD24. Samples were derived from six mice.

2013-07-08 | E-GEOD-46438 | biostudies-arrayexpress

Expression data from Hif 2alpha Knockdown study

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2010-07-29 | E-GEOD-22575 | biostudies-arrayexpress

Disruption of STAT3 signaling promotes KRAS induced lung tumorigenesis

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Comparative Analysis of the Tumor Immune-Microenvironment of Primary and Brain Metastases of Non-Small-Cell Lung Cancer

Project description:To evaluate the characteristics of the tumor immune-microenvironment in brain metastases of non-small-cell lung cancer (NSCLC), we investigated the immunophenotype of primary NSCLC and its brain metastasis.

2021-01-11 | GSE161116 | GEO

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