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  • 1
    Online Resource
    Online Resource
    Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti–PD-1 response in NSCLC
    Life Science Alliance, LLC ; 2019
    In:  Life Science Alliance Vol. 2, No. 3 ( 2019-06), p. e201900328-
    Details
    In: Life Science Alliance, Life Science Alliance, LLC, Vol. 2, No. 3 ( 2019-06), p. e201900328-
    Abstract: Targeting PD-1/PD-L1 is only effective in ∼20% of lung cancer patients, but determinants of this response are poorly defined. We previously observed differential responses of two murine K-Ras–mutant lung cancer cell lines to anti–PD-1 therapy: CMT167 tumors were eliminated, whereas Lewis Lung Carcinoma (LLC) tumors were resistant. The goal of this study was to define mechanism(s) mediating this difference. RNA sequencing analysis of cancer cells recovered from lung tumors revealed that CMT167 cells induced an IFNγ signature that was blunted in LLC cells. Silencing Ifngr1 in CMT167 resulted in tumors resistant to IFNγ and anti–PD-1 therapy. Conversely, LLC cells had high basal expression of SOCS1, an inhibitor of IFNγ. Silencing Socs1 increased response to IFNγ in vitro and sensitized tumors to anti–PD-1. This was associated with a reshaped tumor microenvironment, characterized by enhanced T cell infiltration and enrichment of PD-L1 hi myeloid cells. These studies demonstrate that targeted enhancement of tumor-intrinsic IFNγ signaling can induce a cascade of changes associated with increased therapeutic vulnerability.
    Type of Medium: Online Resource
    ISSN: 2575-1077
    URL: Article
    DOI: 10.26508/lsa.201900328
    Language: English
    Publisher: Life Science Alliance, LLC
    Publication Date: 2019
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  • 2
    Online Resource
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    Targeting DDR2 enhances tumor response to anti–PD-1 immunotherapy
    American Association for the Advancement of Science (AAAS) ; 2019
    In:  Science Advances Vol. 5, No. 2 ( 2019-02)
    Details
    In: Science Advances, American Association for the Advancement of Science (AAAS), Vol. 5, No. 2 ( 2019-02)
    Abstract: While a fraction of cancer patients treated with anti–PD-1 show durable therapeutic responses, most remain unresponsive, highlighting the need to better understand and improve these therapies. Using an in vivo screening approach with a customized shRNA pooled library, we identified DDR2 as a leading target for the enhancement of response to anti–PD-1 immunotherapy. Using isogenic in vivo murine models across five different tumor histologies—bladder, breast, colon, sarcoma, and melanoma—we show that DDR2 depletion increases sensitivity to anti–PD-1 treatment compared to monotherapy. Combination treatment of tumor-bearing mice with anti–PD-1 and dasatinib, a tyrosine kinase inhibitor of DDR2, led to tumor load reduction. RNA-seq and CyTOF analysis revealed higher CD8 + T cell populations in tumors with DDR2 depletion and those treated with dasatinib when either was combined with anti–PD-1 treatment. Our work provides strong scientific rationale for targeting DDR2 in combination with PD-1 inhibitors.
    Type of Medium: Online Resource
    ISSN: 2375-2548
    URL: Article
    DOI: 10.1126/sciadv.aav2437
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2019
    detail.hit.zdb_id: 2810933-8
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  • 3
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    Abstract IA10: Developing rational combination therapy with checkpoint inhibitors
    American Association for Cancer Research (AACR) ; 2020
    In:  Clinical Cancer Research Vol. 26, No. 15_Supplement ( 2020-08-01), p. IA10-IA10
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 26, No. 15_Supplement ( 2020-08-01), p. IA10-IA10
    Abstract: Targeting antibodies to programmed cell death protein-1 (PD-1) is an effective treatment across multiple cancer types. While a subset of patients receiving these therapies experience favorable responses, many still show disease progression, highlighting the importance of other mechanisms influencing immune responsiveness in these tumors. Therefore, combining therapies that enhance antitumor immunity has been an area of great interest to the entire cancer community. We have recently tackled this challenge in the rapidly evolving field of cancer immunotherapy by using in vivo functional genomics to identify genes whose inhibition potentiates the response to anti-PD-1 immunotherapy. Using an in vivo screening approach with a customized shRNA pooled library, we identified a number of candidates including DDR2 as promising targets for the enhancement of response to anti-PD-1 immunotherapy. In the case of DDR2, using isogenic in vivo murine models across five different tumor histologies—bladder, breast, colon, sarcoma, and melanoma—we show that DDR2 depletion increases sensitivity to anti-PD-1 treatment compared to monotherapy. Combination treatment of tumor-bearing mice with anti-PD-1 and dasatinib, a tyrosine kinase inhibitor of DDR2, also led to tumor load reduction and in some cases, complete clearance. RNAseq and CyTOF analysis revealed higher CD8+ T-cell populations in tumors with DDR2 depletion and those treated with dasatinib when either was combined with anti-PD-1 treatment. Our work provides strong scientific rationale for targeting DDR2 in combination with PD-1 inhibitors. In addition, a number of other potential druggable targets have been identified in our screen that we are currently pursuing. Citation Format: Megan M. Tu, Francis Y. F. Lee, Robert T. Jones, Abigail K. Kimball, Elizabeth Saravia, Robert F. Graziano, Brianne Coleman, Krista Menard, Jun Yan, Erin Michaud, Han Chang, Hany A. Abdel-Hafiz, Andrii I. Rozhok, Jason E. Duex, Neeraj Agarwal, Ana Chauca-Diaz, Linda K. Johnson, Terry L. Ng, John C. Cambier, Eric T. Clambey, James C. Costello, Alan J. Korman, Dan Theodorescu. Developing rational combination therapy with checkpoint inhibitors [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA10.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.BLADDER19-IA10
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 4
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    Abstract 4085: DDR2 inhibition enhances response to anti-PD-1 immunotherapy
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4085-4085
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4085-4085
    Abstract: Therapies targeting PD-1 are used in multiple cancer types. While a fraction of patients show durable therapeutic responses, most remain unresponsive, highlighting an urgent need to better understand and improve these therapies. Using an in vivo screening approach with a customized shRNA pooled library, we identified DDR2 as a leading target for the enhancement of response to anti-PD-1 immunotherapy. Using isogenic in vivo murine models across five different tumor histologies, bladder, breast, colon, sarcoma and melanoma, we show that DDR2 depletion increases sensitivity to anti-PD-1 treatment compared to monotherapy. Combination treatment of tumor-bearing mice with anti-PD-1 and dasatinib, a tyrosine kinase inhibitor of DDR2, also led to tumor load reduction and in some cases, complete clearance. RNAseq and CyTOF analysis revealed higher CD8+ T cell populations in tumors with DDR2 depletion and those treated with dasatinib when either was combined with anti-PD-1 treatment. Our work provides strong scientific rationale for targeting DDR2 in combination with PD-1 inhibitors. Citation Format: Megan M. Tu, Francis Y. Lee, Robert T. Jones, Abigail K. Kimball, Elizabeth Saravia, Robert F. Graziano, Brianne Coleman, Krista Menard, Jun Yan, Erin Michaud, Han Chang, Hany A. Abdel-Hafiz, Andrii I. Rozhok, Jason E. Duex, Neeraj Agarwal, Ana Chauca-Diaz, Linda K. Johnson, Terry L. Ng, John C. Cambier, Eric T. Clambey, James C. Costello, Alan J. Korman, Dan Theodorescu. DDR2 inhibition enhances response to anti-PD-1 immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4085.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-4085
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
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    Cancer cell-intrinsic expression of MHC II in lung cancer cell lines is actively restricted by MEK/ERK signaling and epigenetic mechanisms
    BMJ ; 2020
    In:  Journal for ImmunoTherapy of Cancer Vol. 8, No. 1 ( 2020-04), p. e000441-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 8, No. 1 ( 2020-04), p. e000441-
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2019-000441
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 2719863-7
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  • 6
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    High-Dimensional Characterization of IL-10 Production and IL-10–Dependent Regulation during Primary Gammaherpesvirus Infection
    The American Association of Immunologists ; 2019
    In:  ImmunoHorizons Vol. 3, No. 3 ( 2019-03-01), p. 94-109
    Details
    In: ImmunoHorizons, The American Association of Immunologists, Vol. 3, No. 3 ( 2019-03-01), p. 94-109
    Abstract: IL-10 is a potent immunomodulatory cytokine produced by multiple cell types to restrain immune activation. Many herpesviruses use the IL-10 pathway to facilitate infection, but how endogenous IL-10 is regulated during primary infection in vivo remains poorly characterized. In this study, we infected mice with murine gammaherpesvirus 68 (γHV68) and analyzed the production and genetic contribution of IL-10 by mass cytometry (cytometry by time-of-flight) analysis. γHV68 infection elicited a breadth of effector CD4 T cells in the lungs of acutely infected mice, including a highly activated effector subset that coexpressed IFN-γ, TNF-α, and IL-10. By using IL-10 GFP transcriptional reporter mice, we identified that IL-10 was primarily expressed within CD4 T cells during acute infection in the lungs. IL10gfp-expressing CD4 T cells were highly proliferative and characterized by the expression of multiple coinhibitory receptors, including PD-1 and LAG-3. When we analyzed acute γHV68 infection of IL-10–deficient mice, we found that IL-10 limits the frequency of both myeloid and effector CD4 T cell subsets in the infected lung, with minimal changes at a distant mucosal site. These data emphasize the unique insights that high-dimensional analysis can afford in investigating antiviral immunity and provide new insights into the breadth, phenotype, and function of IL-10–expressing effector CD4 T cells during acute virus infection.
    Type of Medium: Online Resource
    ISSN: 2573-7732
    URL: Article
    DOI: 10.4049/immunohorizons.1800088
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2019
    detail.hit.zdb_id: 2882729-6
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  • 7
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    Multidimensional analysis of Gammaherpesvirus RNA expression reveals unexpected heterogeneity of gene expression
    Public Library of Science (PLoS) ; 2019
    In:  PLOS Pathogens Vol. 15, No. 6 ( 2019-6-5), p. e1007849-
    Details
    In: PLOS Pathogens, Public Library of Science (PLoS), Vol. 15, No. 6 ( 2019-6-5), p. e1007849-
    Type of Medium: Online Resource
    ISSN: 1553-7374
    URL: Article
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    DOI: 10.1371/journal.ppat.1007849
    DOI: 10.1371/journal.ppat.1007849.g001
    DOI: 10.1371/journal.ppat.1007849.g002
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    DOI: 10.1371/journal.ppat.1007849.s001
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    DOI: 10.1371/journal.ppat.1007849.s005
    DOI: 10.1371/journal.ppat.1007849.s006
    Language: English
    Publisher: Public Library of Science (PLoS)
    Publication Date: 2019
    detail.hit.zdb_id: 2205412-1
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  • 8
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    Tissue-specific requirements for IL-10 in maintaining homeostasis in response to chronic virus infection
    The American Association of Immunologists ; 2017
    In:  The Journal of Immunology Vol. 198, No. 1_Supplement ( 2017-05-01), p. 78.24-78.24
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 1_Supplement ( 2017-05-01), p. 78.24-78.24
    Abstract: Herpesviruses have co-evolved with their hosts for million of years, establishing an intimate balancing act of lifelong infection with minimal damage to the host. Interleukin (IL)-10 is a major inhibitory cytokine that has been usurped by many herpesviruses to facilitate infection. Here we tested the consequence of IL-10 deficiency on the outcome of murine gammaherpesvirus 68 (γHV68) infection, a small animal model of γHV pathogenesis. While IL-10 deficiency had minimal impact on the control of virus infection, IL-10 deficient mice showed hyper-activation of the immune response with increased levels of T cell activation, effector T cells and prolonged neutrophilia in the infected lung. IL-10 further had a non-redundant role in limiting intestinal inflammation with chronically infected mice showing a prolonged failure to thrive following infection, associated with enhanced colonic Th1 responses. CD4 T cells were a prominent source of IL10 during acute and chronic infection, with IL10+ interferon-gamma+ FoxP3- type 1 regulatory CD4 T cells as the major early source of IL10. High-dimensional mass cytometric analysis of IL10 expressing cells, and IL10 responsive cells, identified a constellation of phenotypes that correlate with robust IL10 expression, and further identified direct and indirect targets of IL10. In total, these data demonstrate the context dependent role of IL10 in constraining the antiviral host response and identify IL10-dependent and –independent regulatory pathways in regulating chronic herpesvirus infection. This research was funded by grants from the American Heart Association, Crohn’s and Colitis Foundation of America and the UC Department of Anesthesiology (ETC).
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.198.Supp.78.24
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2017
    detail.hit.zdb_id: 1475085-5
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  • 9
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    Tumor cell-intrinsic MHC class II expression as a determinant of immunotherapy responsiveness in an orthotopic mouse model of non-small cell lung cancer
    The American Association of Immunologists ; 2018
    In:  The Journal of Immunology Vol. 200, No. 1_Supplement ( 2018-05-01), p. 57.1-57.1
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 200, No. 1_Supplement ( 2018-05-01), p. 57.1-57.1
    Abstract: Lung cancer is the leading cause of cancer-related deaths worldwide and the second most common cancer among both men and women in the United States. Immunotherapy regimens that disrupt the inhibitory PD-1/PD-L1 axis have recently emerged as promising treatments that can unleash anti-tumor immunity against a wide range of cancers, including a subset of lung cancers. How these therapies elicit potent anti-tumor immunity remains controversial, with markers for immunotherapy-sensitivity still an active area of investigation. To study determinants of lung cancer growth in vivo we studied two orthotopic mouse models of non-small cell lung cancer (NSCLC). These Kras-mutant tumor lines dramatically differ in their response to immunotherapy: CMT167 tumor cells are exquisitely susceptible to PD-1/PD-L1 targeted immunotherapy whereas LLC tumor cells are immunotherapy-resistant. Immunotherapy-sensitive cells showed induction of the MHC class II antigen processing and presentation pathway in vitro and in vivo, and were capable of stimulating CD4 T cells directly in ex vivo co-culture. To study the impact of tumor cell-intrinsic MHC class II induction, we used RNA interference to knockdown CIITA, a transcriptional inducer of the MHC class II pathway. CIITA knockdown in immunotherapy-sensitive cells impaired the induction of tumor cell-intrinsic MHC class II in vitro and abrogated CD4 T cell stimulation in co-culture. CIITA knockdown further converted tumors from immunotherapy-sensitive to immunotherapy-resistant. These studies identify tumor cell-intrinsic expression of MHC class II as a potential direct target for CD4 T cell recognition that may promote sensitivity to PD-1/PD-L1 blockade.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.200.Supp.57.1
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2018
    detail.hit.zdb_id: 1475085-5
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  • 10
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    A Beginner’s Guide to Analyzing and Visualizing Mass Cytometry Data
    The American Association of Immunologists ; 2018
    In:  The Journal of Immunology Vol. 200, No. 1 ( 2018-01-01), p. 3-22
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 200, No. 1 ( 2018-01-01), p. 3-22
    Abstract: Mass cytometry has revolutionized the study of cellular and phenotypic diversity, significantly expanding the number of phenotypic and functional characteristics that can be measured at the single-cell level. This high-dimensional analysis platform has necessitated the development of new data analysis approaches. Many of these algorithms circumvent traditional approaches used in flow cytometric analysis, fundamentally changing the way these data are analyzed and interpreted. For the beginner, however, the large number of algorithms that have been developed, as well as the lack of consensus on best practices for analyzing these data, raise multiple questions: Which algorithm is the best for analyzing a dataset? How do different algorithms compare? How can one move beyond data visualization to gain new biological insights? In this article, we describe our experiences as recent adopters of mass cytometry. By analyzing a single dataset using five cytometry by time-of-flight analysis platforms (viSNE, SPADE, X-shift, PhenoGraph, and Citrus), we identify important considerations and challenges that users should be aware of when using these different methods and common and unique insights that can be revealed by these different methods. By providing annotated workflow and figures, these analyses present a practical guide for investigators analyzing high-dimensional datasets. In total, these analyses emphasize the benefits of integrating multiple cytometry by time-of-flight analysis algorithms to gain complementary insights into these high-dimensional datasets.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1701494
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2018
    detail.hit.zdb_id: 1475085-5
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