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  • 1
    Online Resource
    Online Resource
    Abstract 65: Therapeutically increasing MHC-I expression potentiates immune checkpoint blockade
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 65-65
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 65-65
    Abstract: Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Here, we combined FACS-based genome-wide CRISPR screens with a data-mining approach to identify drugs that can upregulate MHC-I without inducing PD-L1. CRISPR screening identified TRAF3, a critical suppressor of the NF-κB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3-knockout (Traf3-KO) gene expression signature is associated with better survival in ICB-naive cancer patients and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified SMAC mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T-cell-dependent killing, and synergizes with ICB. Our findings provide preclinical rationale for treating tumors expressing low MHC-I expression with SMAC mimetics to enhance sensitivity to immunotherapy. The approach used in this study can be generalized to identify other drugs that enhance immunotherapy efficacy. Citation Format: Shengqing Gu, Wubing Zhang, Xiaoqing Wang, Peng Jiang, Nicole Traugh, Ziyi Li, Clifford Meyer, Blair Stewig, Yingtian Xie, Xia Bu, Michael Manos, Alba Font-Tello, Evisa Gjini, Ana Lako, Klothilda Lim, Jake Conway, Alok Tewari, Zexian Zeng, Avinash Das Sahu, Collin Tokheim, Jason L. Weirather, Jingxin Fu, Yi Zhang, Benjamin Kroger, Jin Hua Liang, Paloma Cejas, Gordon J. Freeman, Scott J. Rodig, Henry Long, Benjamin E. Gewurz, F. Stephen Hodi, Myles Brown, X. Shirley Liu. Therapeutically increasing MHC-I expression potentiates immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 65.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-65
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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    detail.hit.zdb_id: 410466-3
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  • 2
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    Online Resource
    Abstract A83: Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Immunology Research Vol. 8, No. 3_Supplement ( 2020-03-01), p. A83-A83
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 8, No. 3_Supplement ( 2020-03-01), p. A83-A83
    Abstract: T-cell dysfunction in the tumor microenvironment (TME) is a hallmark of many cancers. Reinvigoration of T-cell function by PD-1 checkpoint blockade can result in striking clinical responses, but is only effective in a minority of patients. The mechanisms by which anti-PD-1 therapy acts on exhausted T cells are not fully understood. Here we show that anti-PD-1 therapy acts on a specific subpopulation of CD8+ tumor-infiltrating lymphocytes (TILs) in melanoma mouse models, which can also be found in patients with melanoma. Exhausted CD8+ TILs contain a subpopulation of “progenitor exhausted” T cells with critical functional attributes that are not shared by the majority “terminally exhausted” TILs: they retain more polyfunctionality, persist following transfer into tumor-bearing mice, and differentiate to repopulate terminally exhausted TILs in the TME. As a result, progenitor exhausted CD8+ TILs are better able to control tumor growth than terminally exhausted cells. Progenitor exhausted, but not terminally exhausted, CD8+ TILs can respond to anti-PD-1 therapy. Melanoma patients with a higher percentage of progenitor exhausted cells have a longer duration of response to checkpoint blockade therapy. Therefore, approaches to expand progenitor exhausted CD8+ T cells in the tumor microenvironment may be an important component of improving checkpoint blockade response. Citation Format: Brian C. Miller, Debattama R. Sen, Rose Al Abosy, Kevin Bi, Yamini Virkud, Martin W. LaFleur, Kathleen B. Yates, Ana Lako, Kristen Felt, Girish S. Naik, Michael Manos, Evisa Gjini, Jeffrey J. Ishizuka, F. Stephen Hodi, Scott J. Rodig, Arlene H. Sharpe, W. Nicholas Haining. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A83.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.TUMIMM19-A83
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2732517-9
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  • 3
    Online Resource
    Online Resource
    Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade
    Springer Science and Business Media LLC ; 2019
    In:  Nature Immunology Vol. 20, No. 3 ( 2019-3), p. 326-336
    Details
    In: Nature Immunology, Springer Science and Business Media LLC, Vol. 20, No. 3 ( 2019-3), p. 326-336
    Type of Medium: Online Resource
    ISSN: 1529-2908 , 1529-2916
    URL: Article
    DOI: 10.1038/s41590-019-0312-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2026412-4
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  • 4
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    Online Resource
    Author Correction: Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade
    Springer Science and Business Media LLC ; 2019
    In:  Nature Immunology Vol. 20, No. 11 ( 2019-11), p. 1556-1556
    Details
    In: Nature Immunology, Springer Science and Business Media LLC, Vol. 20, No. 11 ( 2019-11), p. 1556-1556
    Type of Medium: Online Resource
    ISSN: 1529-2908 , 1529-2916
    URL: Article
    DOI: 10.1038/s41590-019-0528-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2026412-4
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  • 5
    Online Resource
    Online Resource
    Therapeutically Increasing MHC-I Expression Potentiates Immune Checkpoint Blockade
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Discovery Vol. 11, No. 6 ( 2021-06-01), p. 1524-1541
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 11, No. 6 ( 2021-06-01), p. 1524-1541
    Abstract: Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Here, we combined FACS-based genome-wide CRISPR screens with a data-mining approach to identify drugs that can upregulate MHC-I without inducing PD-L1. CRISPR screening identified TRAF3, a suppressor of the NFκB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3-knockout gene expression signature is associated with better survival in ICB-naïve patients with cancer and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified Second Mitochondria-derived Activator of Caspase (SMAC) mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T cell–dependent killing, and adds to ICB efficacy. Our findings provide preclinical rationale for treating tumors expressing low MHC-I expression with SMAC mimetics to enhance sensitivity to immunotherapy. The approach used in this study can be generalized to identify other drugs that enhance immunotherapy efficacy. Significance: MHC-I loss or downregulation in cancer cells is a major mechanism of resistance to T cell–based immunotherapies. Our study reveals that birinapant may be used for patients with low baseline MHC-I to enhance ICB response. This represents promising immunotherapy opportunities given the biosafety profile of birinapant from multiple clinical trials. This article is highlighted in the In This Issue feature, p. 1307
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-20-0812
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2607892-2
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  • 6
    Online Resource
    Online Resource
    Abstract 2701: Functionally specialized subsets of exhausted CD8+ T cells mediate tumor control and differentially respond to checkpoint blockade
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2701-2701
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2701-2701
    Abstract: T cell dysfunction in the tumor microenvironment (TME) is a hallmark of many cancers. Reinvigoration of T cell function by PD-1 checkpoint blockade can result in striking clinical responses, but is only effective in a minority of patients. The basis for T cell dysfunction in the TME, as well as the mechanisms by which anti-PD-1 therapy acts on dysfunctional T cells are not fully understood. Here we show that anti-PD-1 therapy acts on a specific subpopulation of CD8+ tumor-infiltrating lymphocytes (TILs) in melanoma mouse models, which can also be found in patients with melanoma. We find that dysfunctional CD8+ TILs possess canonical epigenetic and transcriptional features of T cell exhaustion, mirroring those seen in chronic viral infection. Similar to chronic viral infection, exhausted CD8+ TILs contain a subpopulation of “progenitor exhausted” T cells that have a distinct regulatory state. Progenitor exhausted TILs also have critical functional attributes that are not shared by the majority “terminally exhausted” TILs: they retain more polyfunctionality, persist following transfer into tumor-bearing mice, and differentiate to repopulate terminally exhausted TILs in the TME. As a result, progenitor exhausted CD8+ TILs are better able to control tumor growth than terminally exhausted cells. Progenitor exhausted, but not terminally exhausted, CD8+ TILs can respond to anti-PD-1 therapy but this occurs without reversion of their exhausted epigenetic state. Human melanomas contain CD8+ T cells with a progenitor exhausted phenotype and patients with a higher fraction of this subpopulation in their tumors have a significantly longer duration of response to combination checkpoint blockade therapy. Therefore, approaches to expand progenitor exhausted CD8+ T cells in the tumor microenvironment may be an important component of improving checkpoint blockade response. Citation Format: Brian C. Miller, Debattama R. Sen, Rose Al Abosy, Kevin Bi, Yamini V. Virkud, Martin W. LaFleur, Kathleen B. Yates, Ana Lako, Kristen Felt, Girish S. Naik, Michael Manos, Evisa Gjini, F. Stephen Hodi, Scott J. Rodig, Arlene H. Sharpe, W. Nicholas Haining. Functionally specialized subsets of exhausted CD8+ T cells mediate tumor control and differentially respond to checkpoint blockade [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 2701.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-2701
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
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    Online Resource
    Angiopoietin-2 as a Biomarker and Target for Immune Checkpoint Therapy
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Immunology Research Vol. 5, No. 1 ( 2017-01-01), p. 17-28
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 5, No. 1 ( 2017-01-01), p. 17-28
    Abstract: Immune checkpoint therapies targeting CTLA-4 and PD-1 have proven effective in cancer treatment. However, the identification of biomarkers for predicting clinical outcomes and mechanisms to overcome resistance remain as critical needs. Angiogenesis is increasingly appreciated as an immune modulator with potential for combinatorial use with checkpoint blockade. Angiopoietin-2 (ANGPT2) is an immune target in patients and is involved in resistance to anti-VEGF treatment with the monoclonal antibody bevacizumab. We investigated the predictive and prognostic value of circulating ANGPT2 in metastatic melanoma patients receiving immune checkpoint therapy. High pretreatment serum ANGPT2 was associated with reduced overall survival in CTLA-4 and PD-1 blockade–treated patients. These treatments also increased serum ANGPT2 in many patients early after treatment initiation, whereas ipilimumab plus bevacizumab treatment decreased serum concentrations. ANGPT2 increases were associated with reduced response and/or overall survival. Ipilimumab increased, and ipilimumab plus bevacizumab decreased, tumor vascular ANGPT2 expression in a subset of patients, which was associated with increased and decreased tumor infiltration by CD68+ and CD163+ macrophages, respectively. In vitro, bevacizumab blocked VEGF-induced ANGPT2 expression in tumor-associated endothelial cells, whereas ANGPT2 increased PD-L1 expression on M2-polarized macrophages. Treatments elicited long-lasting and functional antibody responses to ANGPT2 in a subset of patients receiving clinical benefit. Our findings suggest that serum ANGPT2 may be considered as a predictive and prognostic biomarker for immune checkpoint therapy and may contribute to treatment resistance via increasing proangiogenic and immunosuppressive activities in the tumor microenvironment. Targeting ANGPT2 provides a rational combinatorial approach to improve the efficacy of immune therapy. Cancer Immunol Res; 5(1); 17–28. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-16-0206
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 8
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    Online Resource
    Abstract A216: Functionally specialized subsets of exhausted CD8+ T-cells mediate tumor control and response to checkpoint blockade
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Immunology Research Vol. 7, No. 2_Supplement ( 2019-02-01), p. A216-A216
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 7, No. 2_Supplement ( 2019-02-01), p. A216-A216
    Abstract: T-cell dysfunction in the tumor microenvironment (TME) is a hallmark of many cancers. Reinvigoration of T-cell function by PD-1 checkpoint blockade can result in striking clinical responses, but is effective only in a minority of patients. The basis for T-cell dysfunction in the TME, as well as the mechanisms by which anti-PD-1 therapy acts on dysfunctional T-cells are not fully understood. Here we show that anti-PD-1 therapy acts on a specific subpopulation of CD8+ tumor-infiltrating lymphocytes (TILs) in melanoma mouse models as well as patients with melanoma. We find that dysfunctional CD8+ TILs possess canonical epigenetic and transcriptional features of T-cell exhaustion, mirroring those seen in chronic viral infection. Similar to chronic viral infection, exhausted CD8+ TILs contain a subpopulation of “stem-like exhausted” T-cells that have a distinct regulatory state. Stem-like exhausted TILs also have critical functional attributes that are not shared by the majority “terminally exhausted” TILs: they retain more polyfunctionality, persist following transfer into tumor-bearing mice, and differentiate to repopulate terminally exhausted TILs in the TME. As a result, stem-like exhausted CD8+ TILs are better able to control tumor growth than terminally exhausted cells. Stem-like exhausted, but not terminally exhausted, CD8+ TILs can respond to anti-PD-1 therapy without reversion of their exhausted epigenetic state. CD8+ T-cells with a stem-like exhausted phenotype can be found in human melanoma samples and patients with a higher fraction of this subpopulation in their tumors have a significantly longer duration of response to combination checkpoint blockade therapy. Responsiveness to checkpoint blockade is therefore restricted to a subpopulation of exhausted TILs that retain specific functional properties which enable them to control tumors. Approaches to expand stem-like exhausted CD8+ T-cells in the tumor microenvironment may be an important component of improving checkpoint blockade response. Citation Format: Debattama R. Sen, Brian C. Miller, Rose Al Abosy, Kevin Bi, Martin W. LaFleur, Kathleen B. Yates, Ana Lako, Kristen D. Felt, Girish S. Naik, Michael Manos, Evisa Gjini, Yamini V. Virkud, Stephen Hodi, Scott J. Rodig, Arlene H. Sharpe, W. Nicholas Haining. Functionally specialized subsets of exhausted CD8+ T-cells mediate tumor control and response to checkpoint blockade [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A216.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A216
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 9
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    Online Resource
    Inactivation of Fbxw7 Impairs dsRNA Sensing and Confers Resistance to PD-1 Blockade
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Discovery Vol. 10, No. 9 ( 2020-09-01), p. 1296-1311
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 10, No. 9 ( 2020-09-01), p. 1296-1311
    Abstract: The molecular mechanisms leading to resistance to PD-1 blockade are largely unknown. Here, we characterize tumor biopsies from a patient with melanoma who displayed heterogeneous responses to anti–PD-1 therapy. We observe that a resistant tumor exhibited a loss-of-function mutation in the tumor suppressor gene FBXW7, whereas a sensitive tumor from the same patient did not. Consistent with a functional role in immunotherapy response, inactivation of Fbxw7 in murine tumor cell lines caused resistance to anti–PD-1 in immunocompetent animals. Loss of Fbxw7 was associated with altered immune microenvironment, decreased tumor-intrinsic expression of the double-stranded RNA (dsRNA) sensors MDA5 and RIG-I, and diminished induction of type I IFN and MHC-I expression. In contrast, restoration of dsRNA sensing in Fbxw7-deficient cells was sufficient to sensitize them to anti–PD-1. Our results thus establish a new role for the commonly inactivated tumor suppressor FBXW7 in viral sensing and sensitivity to immunotherapy. Significance: Our findings establish a role of the commonly inactivated tumor suppressor FBXW7 as a genomic driver of response to anti–PD-1 therapy. Fbxw7 loss promotes resistance to anti–PD-1 through the downregulation of viral sensing pathways, suggesting that therapeutic reactivation of these pathways could improve clinical responses to checkpoint inhibitors in genomically defined cancer patient populations. This article is highlighted in the In This Issue feature, p. 1241
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-19-1416
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2607892-2
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