20 results on '"Creg J, Workman"'
Search Results
2. Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein
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Xiaobo Mao, Hao Gu, Donghoon Kim, Yasuyoshi Kimura, Ning Wang, Enquan Xu, Ramhari Kumbhar, Xiaotian Ming, Haibo Wang, Chan Chen, Shengnan Zhang, Chunyu Jia, Yuqing Liu, Hetao Bian, Senthilkumar S. Karuppagounder, Fatih Akkentli, Qi Chen, Longgang Jia, Heehong Hwang, Su Hyun Lee, Xiyu Ke, Michael Chang, Amanda Li, Jun Yang, Cyrus Rastegar, Manjari Sriparna, Preston Ge, Saurav Brahmachari, Sangjune Kim, Shu Zhang, Yasushi Shimoda, Martina Saar, Haiqing Liu, Sin Ho Kweon, Mingyao Ying, Creg J. Workman, Dario A. A. Vignali, Ulrike C. Muller, Cong Liu, Han Seok Ko, Valina L. Dawson, and Ted M. Dawson
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Science - Abstract
Abstract Pathologic α-synuclein (α-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid β precursor-like protein 1 (Aplp1) interacts with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic α-syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by α-syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of α-syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by α-syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for α-syn PFF induced pathology deepens our insight about molecular mechanisms of cell-to-cell transmission of pathologic α-syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinson’s disease and related α-synucleinopathies.
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- 2024
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3. Lymphocyte‐Activation Gene 3 Facilitates Pathological Tau Neuron‐to‐Neuron Transmission
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Chan Chen, Ramhari Kumbhar, Hu Wang, Xiuli Yang, Kundlik Gadhave, Cyrus Rastegar, Yasuyoshi Kimura, Adam Behensky, Sumasri Kotha, Grace Kuo, Sruthi Katakam, Deok Jeong, Liang Wang, Anthony Wang, Rong Chen, Shu Zhang, Lingtao Jin, Creg J. Workman, Dario A. A. Vignali, Olga Pletinkova, Hongpeng Jia, Weiyi Peng, David W. Nauen, Philip C. Wong, Javier Redding‐Ochoa, Juan C. Troncoso, Mingyao Ying, Valina L. Dawson, Ted M. Dawson, and Xiaobo Mao
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lymphocyte‐activation gene 3 ,cell‐to‐cell transmission ,receptor ,Tau ,Tau preformed fibrils ,Science - Abstract
Abstract The spread of prion‐like protein aggregates is a common driver of pathogenesis in various neurodegenerative diseases, including Alzheimer's disease (AD) and related Tauopathies. Tau pathologies exhibit a clear progressive spreading pattern that correlates with disease severity. Clinical observation combined with complementary experimental studies has shown that Tau preformed fibrils (PFF) are prion‐like seeds that propagate pathology by entering cells and templating misfolding and aggregation of endogenous Tau. While several cell surface receptors of Tau are known, they are not specific to the fibrillar form of Tau. Moreover, the underlying cellular mechanisms of Tau PFF spreading remain poorly understood. Here, it is shown that the lymphocyte‐activation gene 3 (Lag3) is a cell surface receptor that binds to PFF but not the monomer of Tau. Deletion of Lag3 or inhibition of Lag3 in primary cortical neurons significantly reduces the internalization of Tau PFF and subsequent Tau propagation and neuron‐to‐neuron transmission. Propagation of Tau pathology and behavioral deficits induced by injection of Tau PFF in the hippocampus and overlying cortex are attenuated in mice lacking Lag3 selectively in neurons. These results identify neuronal Lag3 as a receptor of pathologic Tau in the brain,and for AD and related Tauopathies, a therapeutic target.
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- 2024
- Full Text
- View/download PDF
4. IFNγ-induction of TH1-like regulatory T cells controls antiviral responses
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Angela M. Gocher-Demske, Jian Cui, Andrea L. Szymczak-Workman, Kate M. Vignali, Julianna N. Latini, Gwen P. Pieklo, Jesse C. Kimball, Lyndsay Avery, Ellyse M. Cipolla, Brydie R. Huckestein, Lee Hedden, Marlies Meisel, John F. Alcorn, Lawrence P. Kane, Creg J. Workman, and Dario A. A. Vignali
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Immunology ,Immunology and Allergy ,Article - Abstract
Regulatory T (T(reg)) cells are an immunosuppressive population that are required to maintain peripheral tolerance and prevent tissue damage from immunopathology, via anti-inflammatory cytokines, inhibitor receptors and metabolic disruption. Here we show that T(reg) cells acquire an effector-like state, yet remain stable and functional, when exposed to interferon gamma (IFNγ) during infection with lymphocytic choriomeningitis and influenza A virus. T(reg) cell-restricted deletion of the IFNγ receptor (encoded by Ifngr1), but not the interleukin 12 (IL12) receptor (encoded by Il12rb2), prevented T(H)1-like polarization (decreased expression of T-bet, CXC motif chemokine receptor 3 and IFNγ) and promoted T(H)2-like polarization (increased expression of GATA-3, CCR4 and IL4). T(H)1-like T(reg) cells limited CD8(+) T cell effector function, proliferation and memory formation during acute and chronic infection. These findings provide fundamental insights into how T(reg) cells sense inflammatory cues from the environment (such as IFNγ) during viral infection to provide guidance to the effector immune response. This regulatory circuit prevents prolonged immunoinflammatory responses and shapes the quality and quantity of the memory T cell response.
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- 2023
5. Neuronally expressed PDL1, not PD1, suppresses acute nociception
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Kimberly A. Meerschaert, Brian S. Edwards, Ariel Y. Epouhe, Bahiyyah Jefferson, Robert Friedman, Olivia L. Babyok, Jamie K. Moy, Faith Kehinde, Chang Liu, Creg J. Workman, Dario A.A. Vignali, Kathryn M. Albers, H. Richard Koerber, Michael S. Gold, Brian M. Davis, Nicole N. Scheff, and Jami L. Saloman
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Nociception ,Mice ,Behavioral Neuroscience ,Endocrine and Autonomic Systems ,Immunology ,Animals ,Calcium ,RNA, Messenger ,Capsaicin ,B7-H1 Antigen - Abstract
PDL1 is a protein that induces immunosuppression by binding to PD1 expressed on immune cells. In line with historical studies, we found that membrane-bound PD1 expression was largely restricted to immune cells; PD1 was not detectable at either the mRNA or protein level in peripheral neurons using single neuron qPCR, immunolabeling and flow cytometry. However, we observed widespread expression of PDL1 in both sensory and sympathetic neurons that could have important implications for patients receiving immunotherapies targeting this pathway that include unexpected autonomic and sensory related effects. While signaling pathways downstream of PD1 are well established, little to no information is available regarding the intracellular signaling downstream of membrane-bound PDL1 (also known as reverse signaling). Here, we administered soluble PD1 to engage neuronally expressed PDL1 and found that PD1 significantly reduced nocifensive behaviors evoked by algogenic capsaicin. We used calcium imaging to examine the underlying neural mechanism of this reduction and found that exogenous PD1 diminished TRPV1-dependent calcium transients in dissociated sensory neurons. Furthermore, we observed a reduction in membrane expression of TRPV1 following administration of PD1. Exogenous PD1 had no effect on pain-related behaviors in sensory neuron specific PDL1 knockout mice. These data indicate that neuronal PDL1 activation is sufficient to modulate sensitivity to noxious stimuli and as such, may be an important homeostatic mechanism for regulating acute nociception.
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- 2022
6. Pathological Tau transmission initiated by binding lymphocyte-activation gene 3
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Chan Chen, Ramhari Kumbhar, Hu Wang, Xiuli Yang, Kundlik Gadhave, Cyrus Rastegar, Yasuyoshi Kimura, Adam Behensky, Sruthi Katakam, Deok Jeong, Liang Wang, Anthony Wang, Rong Chen, Shu Zhang, Lingtao Jin, Creg J. Workman, Dario A.A. Vignali, Olga Pletinkova, David W. Nauen, Philip C. Wong, Juan C. Troncoso, Mingyao Ying, Valina L. Dawson, Ted M. Dawson, and Xiaobo Mao
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Article - Abstract
The spread of prion-like protein aggregates is believed to be a common driver of pathogenesis in many neurodegenerative diseases. Accumulated tangles of filamentous Tau protein are considered pathogenic lesions of Alzheimer’s disease (AD) and related Tauopathies, including progressive supranuclear palsy, and corticobasal degeneration. Tau pathologies in these illnesses exhibits a clear progressive and hierarchical spreading pattern that correlates with disease severity1, 2. Clinical observation combined with complementary experimental studies3, 4have shown that Tau preformed fibrils (PFF) are prion-like seeds that propagate pathology by entering cells and templating misfolding and aggregation of endogenous Tau. While several receptors of Tau are known, they are not specific to the fibrillar form of Tau. Moreover, the underlying cellular mechanisms of Tau PFF spreading remains poorly understood. Here, we show that the lymphocyte-activation gene 3 (Lag3) is a cell surface receptor that binds to PFF, but not monomer, of Tau. Deletion ofLag3or inhibition of Lag3 in primary cortical neurons significantly reduces the internalization of Tau PFF and subsequent Tau propagation and neuron-to-neuron transmission. Propagation of Tau pathology and behavioral deficits induced by injection of Tau PFF in the hippocampus and overlying cortex are attenuated in mice lackingLag3selectively in neurons. Our results identify neuronal Lag3 as a receptor of pathologic Tau in the brain, and for AD and related Tauopathies a therapeutic target.One Sentence SummaryLag3 is a neuronal receptor specific for Tau PFF, and is required for uptake, propagation and transmission of Tau pathology.
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- 2023
7. Supplementary Data from Systemic Immune Dysfunction in Cancer Patients Driven by IL6 Induction of LAG3 in Peripheral CD8+ T Cells
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Dario A.A. Vignali, Tullia C. Bruno, Robert L. Ferris, Evan J. Lipson, John M. Kirkwood, James G. Herman, Simon C. Watkins, Daniel P. Normolle, Dhivyaa Rajasundaram, Rebekah Dadey, Michael Calderon, Sonali Joyce, Maria Velez, Lauren Oliveri, Sheryl Kunning, Creg J. Workman, Caleb Lampenfeld, Anthony R. Cillo, and Ashwin Somasundaram
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Supplementary Data from Systemic Immune Dysfunction in Cancer Patients Driven by IL6 Induction of LAG3 in Peripheral CD8+ T Cells
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- 2023
8. Data from Systemic Immune Dysfunction in Cancer Patients Driven by IL6 Induction of LAG3 in Peripheral CD8+ T Cells
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Dario A.A. Vignali, Tullia C. Bruno, Robert L. Ferris, Evan J. Lipson, John M. Kirkwood, James G. Herman, Simon C. Watkins, Daniel P. Normolle, Dhivyaa Rajasundaram, Rebekah Dadey, Michael Calderon, Sonali Joyce, Maria Velez, Lauren Oliveri, Sheryl Kunning, Creg J. Workman, Caleb Lampenfeld, Anthony R. Cillo, and Ashwin Somasundaram
- Abstract
Many cancer patients do not develop a durable response to the current standard-of-care immunotherapies, despite substantial advances in targeting immune inhibitory receptors. A potential compounding issue, which may serve as an unappreciated, dominant resistance mechanism, is an inherent systemic immune dysfunction that is often associated with advanced cancer. Minimal response to inhibitory receptor (IR) blockade therapy and increased disease burden have been associated with peripheral CD8+ T-cell dysfunction, characterized by suboptimal T-cell proliferation and chronic expression of IRs (e.g., PD1 and LAG3). Here, we demonstrated that approximately a third of cancer patients analyzed in this study have peripheral CD8+ T cells that expressed robust intracellular LAG3 (LAG3IC), but not surface LAG3 (LAG3SUR) due to a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) cleavage. This is associated with poor disease prognosis and decreased CD8+ T-cell function, which could be partially reversed by anti-LAG3. Systemic immune dysfunction was restricted to CD8+ T cells, including, in some cases, a high percentage of peripheral naïve CD8+ T cells, and was driven by the cytokine IL6 via STAT3. These data suggest that additional studies are warranted to determine if the combination of increased LAG3IC in peripheral CD8+ T cells and elevated systemic IL6 can serve as predictive biomarkers and identify which cancer patients may benefit from LAG3 blockade.
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- 2023
9. Autoreactive CD8+ T cells are restrained by an exhaustion-like program that is maintained by LAG3
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Stephanie Grebinoski, Qianxia Zhang, Anthony R. Cillo, Sasikanth Manne, Hanxi Xiao, Erin A. Brunazzi, Tracy Tabib, Carly Cardello, Christine G. Lian, George F. Murphy, Robert Lafyatis, E. John Wherry, Jishnu Das, Creg J. Workman, and Dario A. A. Vignali
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Immunology ,Immunology and Allergy - Published
- 2022
10. Systemic Immune Dysfunction in Cancer Patients Driven by IL6 Induction of LAG3 in Peripheral CD8+ T Cells
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Ashwin Somasundaram, Anthony R. Cillo, Caleb Lampenfeld, Creg J. Workman, Sheryl Kunning, Lauren Oliveri, Maria Velez, Sonali Joyce, Michael Calderon, Rebekah Dadey, Dhivyaa Rajasundaram, Daniel P. Normolle, Simon C. Watkins, James G. Herman, John M. Kirkwood, Evan J. Lipson, Robert L. Ferris, Tullia C. Bruno, and Dario A.A. Vignali
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Cancer Research ,Antigens, CD ,Interleukin-6 ,Neoplasms ,Immunology ,Humans ,Immunotherapy ,CD8-Positive T-Lymphocytes ,Receptors, Immunologic ,Lymphocyte Activation Gene 3 Protein ,Article - Abstract
Many cancer patients do not develop a durable response to the current standard-of-care immunotherapies, despite substantial advances in targeting immune inhibitory receptors. A potential compounding issue, which may serve as an unappreciated, dominant resistance mechanism, is an inherent systemic immune dysfunction that is often associated with advanced cancer. Minimal response to inhibitory receptor (IR) blockade therapy and increased disease burden have been associated with peripheral CD8+ T-cell dysfunction, characterized by suboptimal T-cell proliferation and chronic expression of IRs (e.g., PD1 and LAG3). Here, we demonstrated that approximately a third of cancer patients analyzed in this study have peripheral CD8+ T cells that expressed robust intracellular LAG3 (LAG3IC), but not surface LAG3 (LAG3SUR) due to a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) cleavage. This is associated with poor disease prognosis and decreased CD8+ T-cell function, which could be partially reversed by anti-LAG3. Systemic immune dysfunction was restricted to CD8+ T cells, including, in some cases, a high percentage of peripheral naïve CD8+ T cells, and was driven by the cytokine IL6 via STAT3. These data suggest that additional studies are warranted to determine if the combination of increased LAG3IC in peripheral CD8+ T cells and elevated systemic IL6 can serve as predictive biomarkers and identify which cancer patients may benefit from LAG3 blockade.
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- 2022
11. LAG3 associates with TCR–CD3 complexes and suppresses signaling by driving co-receptor–Lck dissociation
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Clifford Guy, Diana M. Mitrea, Po-Chien Chou, Jamshid Temirov, Kate M. Vignali, Xueyan Liu, Hui Zhang, Richard Kriwacki, Marcel P. Bruchez, Simon C. Watkins, Creg J. Workman, and Dario A. A. Vignali
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Immunology ,Immunology and Allergy - Published
- 2022
12. Supplementary Tables 1-2, Figures 1-11 from Immune Inhibitory Molecules LAG-3 and PD-1 Synergistically Regulate T-cell Function to Promote Tumoral Immune Escape
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Dario A.A. Vignali, Charles G. Drake, Alan J. Korman, Drew M. Pardoll, Creg J. Workman, Paul J. Utz, Alcides Chaux, Matthew P. Smeltzer, George Netto, Joseph F. Grosso, Stephanie Tangsombatvisit, Chih Long Liu, Peter Vogel, David M. Gravano, Matthew L. Bettini, Christopher J. Nirschl, Mark Selby, Jaishree Bankoti, Monica V. Goldberg, Meghan E. Turnis, and Seng-Ryong Woo
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PDF file - 1.1MB
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- 2023
13. Epitope Mapping of Therapeutic Antibodies Targeting Human LAG3
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Pragati Agnihotri, Arjun K. Mishra, Priyanka Agarwal, Kate M. Vignali, Creg J. Workman, Dario A. A. Vignali, and Roy A. Mariuzza
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Epitopes ,Mice ,Antigens, CD ,T-Lymphocytes ,Immunology ,Immunology and Allergy ,Animals ,Antibodies, Monoclonal ,Humans ,Lymphocyte Activation Gene 3 Protein ,Epitope Mapping ,Single-Chain Antibodies - Abstract
Lymphocyte activation gene 3 protein (LAG3; CD223) is an inhibitory receptor that is highly upregulated on exhausted T cells in tumors and chronic viral infection. Consequently, LAG3 is now a major immunotherapeutic target for the treatment of cancer, and many mAbs against human (h) LAG3 (hLAG3) have been generated to block its inhibitory activity. However, little or no information is available on the epitopes they recognize. We selected a panel of seven therapeutic mAbs from the patent literature for detailed characterization. These mAbs were expressed as Fab or single-chain variable fragments and shown to bind hLAG3 with nanomolar affinities, as measured by biolayer interferometry. Using competitive binding assays, we found that the seven mAbs recognize four distinct epitopes on hLAG3. To localize the epitopes, we carried out epitope mapping using chimeras between hLAG3 and mouse LAG3. All seven mAbs are directed against the first Ig-like domain (D1) of hLAG3, despite their different origins. Three mAbs almost exclusively target a unique 30-residue loop of D1 that forms at least part of the putative binding site for MHC class II, whereas four mainly recognize D1 determinants outside this loop. However, because all the mAbs block binding of hLAG3 to MHC class II, each of the epitopes they recognize must at least partially overlap the MHC class II binding site.
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- 2022
14. Autoreactive CD8
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Stephanie, Grebinoski, Qianxia, Zhang, Anthony R, Cillo, Sasikanth, Manne, Hanxi, Xiao, Erin A, Brunazzi, Tracy, Tabib, Carly, Cardello, Christine G, Lian, George F, Murphy, Robert, Lafyatis, E John, Wherry, Jishnu, Das, Creg J, Workman, and Dario A A, Vignali
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Phenotype ,Neoplasms ,Humans ,Autoimmunity ,CD8-Positive T-Lymphocytes - Abstract
Impaired chronic viral and tumor clearance has been attributed to CD8
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- 2022
15. Therapeutic targeting of regulatory T cells in cancer
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Feng Shan, Ashwin Somasundaram, Tullia C. Bruno, Creg J. Workman, and Dario A.A. Vignali
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Cancer Research ,Oncology ,Neoplasms ,Tumor Microenvironment ,Humans ,Autoimmunity ,Immunotherapy ,T-Lymphocytes, Regulatory - Abstract
The success of immunotherapy in oncology underscores the vital role of the immune system in cancer development. Regulatory T cells (Tregs) maintain a fine balance between autoimmunity and immune suppression. They have multiple roles in the tumor microenvironment (TME) but act particularly in suppressing T cell activation. This review focuses on the detrimental and sometimes beneficial roles of Tregs in tumors, our current understanding of recruitment and stabilization of Tregs within the TME, and current Treg-targeted therapeutics. Research identifying subpopulations of Tregs and their respective functions and interactions within the complex networks of the TME will be crucial to develop the next generation of immunotherapies. Through these advances, Treg-targeted immunotherapy could have important implications for the future of oncology.
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- 2022
16. Molecular Pathways and Mechanisms of LAG3 in Cancer Therapy
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Lawrence P. Andrews, Anthony R. Cillo, Lilit Karapetyan, John M. Kirkwood, Creg J. Workman, and Dario A.A. Vignali
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Cancer Research ,Oncology ,Clinical Trials, Phase III as Topic ,Antigens, CD ,Programmed Cell Death 1 Receptor ,Humans ,Immunotherapy ,CD8-Positive T-Lymphocytes ,Melanoma ,Article - Abstract
Immunotherapy targeting coinhibitory receptors has been highly successful in treating a wide variety of malignancies; however, only a subset of patients exhibits durable responses. The first FDA-approved immunotherapeutics targeting coinhibitory receptors PD1 and CTLA4, alone or in combination, significantly improved survival but were also accompanied by substantial toxicity in combination. The third FDA-approved immune checkpoint inhibitor targets LAG3, a coinhibitory receptor expressed on activated CD4+ and CD8+ T cells, especially in settings of long-term antigenic stimulation, such as chronic viral infection or cancer. Mechanistically, LAG3 expression limits both the expansion of activated T cells and the size of the memory pool, suggesting that LAG3 may be a promising target for immunotherapy. Importantly, the mechanism(s) by which LAG3 contributes to CD8+ T-cell exhaustion may be distinct from those governed by PD1, indicating that the combination of anti-LAG3 and anti-PD1 may synergistically enhance antitumor immunity. Clinical studies evaluating the role of anti-LAG3 in combination with anti-PD1 are underway, and recent phase III trial results in metastatic melanoma demonstrate both the efficacy and safety of this combination. Further ongoing clinical trials are evaluating this combination across multiple tumor types and the adjuvant setting, with accompanying translational and biomarker-focused studies designed to elucidate the molecular pathways that lead to improved antitumor T-cell responses following dual blockade of PD1 and LAG3. Overall, LAG3 plays an important role in limiting T-cell activation and has now become part of the repertoire of combinatorial immunotherapeutics available for the treatment of metastatic melanoma.
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- 2022
17. Antibodies targeting conserved non-canonical antigens and endemic coronaviruses associate with favorable outcomes in severe COVID-19
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Sai Preetham Peddireddy, Syed A. Rahman, Anthony R. Cillo, Godhev Manakkat Vijay, Ashwin Somasundaram, Creg J. Workman, William Bain, Bryan J. McVerry, Barbara Methe, Janet S. Lee, Prabir Ray, Anuradha Ray, Tullia C. Bruno, Dario A. A. Vignali, Georgios D. Kitsios, Alison Morris, Harinder Singh, Aniruddh Sarkar, and Jishnu Das
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SARS-CoV-2 ,Spike Glycoprotein, Coronavirus ,COVID-19 ,Humans ,Antibodies, Viral ,Pandemics ,General Biochemistry, Genetics and Molecular Biology - Abstract
While there have been extensive analyses characterizing cellular and humoral responses across the severity spectrum in COVID-19, predictors of outcomes within severe COVID-19 remain to be comprehensively elucidated. Recently, we identified divergent monocyte states as predictors of outcomes within severe COVID-19, but corresponding humoral profiles of risk have not been delineated. Furthermore, the nature of antibodies (Abs) directed against viral antigens beyond the spike protein or endemic coronavirus antigens and their associations with disease severity and outcomes remain poorly defined. We performed deep molecular profiling of Abs directed against a wide range of antigenic specificities in severe COVID-19 patients admitted to the ICU. The profiles consisted of canonical (S, RBD, N) and non-canonical (orf3a, orf8, nsp3, nps13 and M) antigenic specificities. Notably, multivariate machine learning (ML) models, generated using profiles of Abs directed against canonical or non-canonical antigens, were equally discriminative of recovery and mortality COVID-19 outcomes. In both ML models, survivors were associated with increased virus-specific IgA and IgG3 antibodies and with higher antigen-specific antibody galactosylation. Intriguingly, pre-pandemic healthy controls had cross-reactive Abs directed against nsp13 which is a conserved protein in other alpha and beta coronaviruses. Notably, higher levels of nsp13-specific IgA antibodies were associated with recovery in severe COVID-19. In keeping with these findings, a model built on Ab profiles for endemic coronavirus antigens was also predictive of COVID-19 outcome bifurcation, with higher levels of IgA and IgG3 antibodies against OC43 S and NL63 S being associated with survival. Our results suggest the importance of Abs targeting non-canonical SARS-CoV-2 antigens as well as those directed against endemic coronaviruses in favorable outcomes of severe COVID-19.
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- 2021
18. Interferon Gamma Induction of TH1-like Tregs Controls Anti-viral Responses
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Angela Marie Gocher, Jian Cui, Andrea Szymczak-Workman, Kate Vignali, Julianna N Latini, Gwen P Pieklo, Lyndsay Avery, Ellyse L Cipolla, Brydie R Huckestein, Lee Hedden, Marlies Meisel, John F Alcorn, Lawrence P Kane, Creg J. Workman, and Dario A. A. Vignali
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Immunology ,Immunology and Allergy - Abstract
Regulatory T cells (Tregs) are an immunosuppressive cell population that inhibits immune cell function to maintain peripheral tolerance and homeostasis. We have previously shown that Treg-- response to interferon gamma (IFNγ) is required for response to cancer immunotherapy. We aimed to broaden these findings and determine the impact of Treg response to IFNγ and the IFNγ-inducing cytokine IL12, during viral infection. Mice with Treg-restricted deletion of the IFNγ receptor (IFNGR1, Ifngr1L/LFoxp3Cre-YFP) or the IL12 receptor β2 subunit (IL12Rβ2, Il12b2L/LFoxp3Cre-YFP), were infected with the acute (Armstrong), or chronic (Clone 13), strain of lymphocytic choriomeningitis virus (LCMV). Surprisingly, Treg response to IFNγ but not IL12 induced helper T cell 1 (TH1)-like polarization (expression of T-bet, CXCR3 and IFNγ) of Tregs in mice with chronic LCMV infection. Importantly, this effector-like TH1 Treg state was required for adequate suppression of effector T cells during LCMV infection. Additionally, during LCMV infection, Treg-restricted deletion of IFNGR1 not only prevented TH1-like polarization but also reverted these Tregs to a TH2-like state (expression of GATA-3, CCR4 and IL-4). scRNAseq of viral antigen-specific CD8+ T cells from Clone 13 infected mice showed that Ifngr1-deficient Tregs favored CD8+ T cell memory. These findings were confirmed in an Armstrong/Listeria monocytogenes-GP33 memory model. Further, Ifngr1 deletion from Tregs enhanced response to CD8+ T cell-mediated vaccination when challenged with Clone 13. These findings provide fundamental insight on how Tregs sense inflammatory cues from the environment (IFNγ) during viral infection to prevent overt tissue damage and shape the memory response. Supported by grants from NIH (F32 CA247004-01, T32 CA082084, P01 AI108545, R35 CA263850, R01 CA203689, R01 DK130897, P30 DK120531, P30 CA047904, R01 HL107380, R01 CA206517, R01 AI138504)
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- 2022
19. People critically ill with COVID-19 exhibit peripheral immune profiles predictive of mortality and reflective of SARS-CoV-2 lung viral burden
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Anthony R. Cillo, Ashwin Somasundaram, Feng Shan, Carly Cardello, Creg J. Workman, Georgios D. Kitsios, Ayana T. Ruffin, Sheryl Kunning, Caleb Lampenfeld, Sayali Onkar, Stephanie Grebinoski, Gaurav Deshmukh, Barbara Methe, Chang Liu, Sham Nambulli, Lawrence P. Andrews, W. Paul Duprex, Alok V. Joglekar, Panayiotis V. Benos, Prabir Ray, Anuradha Ray, Bryan J. McVerry, Yingze Zhang, Janet S. Lee, Jishnu Das, Harinder Singh, Alison Morris, Tullia C. Bruno, and Dario A.A. Vignali
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Inflammation ,SARS-CoV-2 ,inflammatory cytokines ,Critical Illness ,gene modules ,inflammatory monocytes ,COVID-19 ,Reproducibility of Results ,severe COVID-19 ,Models, Theoretical ,Viral Load ,Monocytes ,General Biochemistry, Genetics and Molecular Biology ,machine learning ,Report ,single-cell RNAseq ,Cytokines ,Humans ,type I interferon ,Gene Regulatory Networks ,Myeloid Cells ,COVID-19 outcome ,Lung ,Aged - Abstract
Despite extensive analyses, there remains an urgent need to delineate immune cell states that contribute to mortality in critically ill Coronavirus disease 2019 (COVID-19) patients. Here, we present high-dimensional profiling of blood and respiratory samples in severe COVID-19 patients to examine the association between cell-linked molecular features and mortality outcomes. Peripheral transcriptional profiles by single-cell RNAseq based deconvolution of immune states are associated with COVID-19 mortality. Further, persistently high levels of an interferon signaling module in monocytes over time leads to subsequent concerted upregulation of inflammatory cytokines. SARS-CoV-2 infected myeloid cells in the lower respiratory tract upregulate CXCL10, leading to a higher risk of death. Our analysis suggests a pivotal role for viral infected myeloid cells and protracted interferon signaling in severe COVID-19., Graphical Abstract, Cillo et al identify transcriptional profiles in peripheral blood that are associated with mortality in critically ill COVID-19 patients. Inflammatory monocyte signatures are correlated with CXCL10 in plasma and precede upregulation of inflammatory cytokines in blood. SARS-CoV-2-infected macrophages in the respiratory tract expressed CXCL10, linking peripheral and lung immune profiles.
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- 2021
20. 253 PD1 and LAG3 converge to limit polyfunctionality and systemic immunity
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Dario A. A. Vignali, E. John Wherry, Creg J. Workman, Lawrence C. Andrews, and Sasikanth Manne
- Subjects
Pharmacology ,Physics ,Cancer Research ,LAG3 ,Oncology ,Immunology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Molecular Medicine ,Immunology and Allergy ,Systemic immunity ,Limit (mathematics) ,RC254-282 - Abstract
BackgroundTargeting PD1 with monoclonal antibodies has yielded clinical success across a variety of tumor types, yet overcoming inhibitory receptor (IR)-mediated tolerance is essential to improve immunotherapeutic responses. LAG3 co-expresses with PD1 on CD8+ tumor-infiltrating T cells (TIL), signifying a highly exhausted phenotype, and dual PD1/LAG3 blockade in C57BL/6 mice enhances antitumor immunity. As CD8+ TIL is the dominant LAG3-expressing TIL population, it is hypothesized that PD1 and LAG3 synergizes to limit CD8+ TIL function controlling antitumor immunity.MethodsTo understand the cellular and mechanistic basis for PD1/LAG3 synergy, conditional knock-in mice ”surgically dissect” Pdcd1 and/or Lag3 floxed alleles restricted to CD8+ T cells expressing E8ICre.GFP. These mice were crossed with the Pmel transgene to assess PD1 and/or LAG3-sufficient or deficient gp100-specific CD8+ T cell populations. CD8+ Pmel cells were isolated and adoptively transferred into C57BL/6 mice harboring a B16-gp100-overexpressing tumor to observe therapeutic benefit, or to assess T cell functionality within the tumor.ResultsWhile little therapeutic benefit was observed with a prophylactic adoptive transfer of wild-type CD8+ Pmel cells into mice which then received B16-gp100 tumor, there was reduced tumor growth in mice receiving PD1-deficient CD8+ Pmel cells, which was further enhanced in mice receiving PD1/LAG3-deficient CD8+ Pmel cells with long-term tumor-free survival. Likewise, a therapeutic administration of PD1/LAG3-deficient CD8+ Pmel cells into mice once the tumor has been established showed an initial therapeutic benefit, with enhanced survival, that was not demonstrated with adoptive transfer of PD1 or LAG3-deficient, or wild-type, counterparts. Each PD1 and/or LAG3-sufficient or deficient CD8+ Pmel mice were differentially congenically marked to assess each of the four genotypes that can be adoptively transferred into the same host as a ”quad transfer” system. Recovery of these populations within the tumor show that the PD1/LAG3-deficient CD8+ Pmel cells out-compete PD1 or LAG3-deficient, or wild-type, counterparts due to enhanced proliferation (Ki67/BrdU). Furthermore, PD1/LAG3-deficient CD8+ T cells were more functional with increased IFNg and GzmB release observed by flow cytometry.ConclusionsOverall PD1 and LAG3 limit anti-tumor immune effects as removal of both IRs on a gp100 antigen-specific CD8+ T cell population results in reduced B16-gp100 tumor growth and enhanced survival in an adoptive transfer model, as a result of enhanced CD8+ TIL functionality and proliferation. These results provide striking evidence that the development of anti-LAG3 agents in the clinic would yield improved responses with anti-PD1.
- Published
- 2021
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