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  • 1
    Publication Date: 2015-03-11
    Description: Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T-cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires radiation, anti-CTLA4 and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T-regulatory cells (Treg cells), thereby increasing the CD8 T-cell to Treg (CD8/Treg) ratio. Radiation enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while radiation shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T-cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligoclonal T-cell expansion. Similarly to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T-cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumours to escape anti-CTLA4-based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401634/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401634/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Twyman-Saint Victor, Christina -- Rech, Andrew J -- Maity, Amit -- Rengan, Ramesh -- Pauken, Kristen E -- Stelekati, Erietta -- Benci, Joseph L -- Xu, Bihui -- Dada, Hannah -- Odorizzi, Pamela M -- Herati, Ramin S -- Mansfield, Kathleen D -- Patsch, Dana -- Amaravadi, Ravi K -- Schuchter, Lynn M -- Ishwaran, Hemant -- Mick, Rosemarie -- Pryma, Daniel A -- Xu, Xiaowei -- Feldman, Michael D -- Gangadhar, Tara C -- Hahn, Stephen M -- Wherry, E John -- Vonderheide, Robert H -- Minn, Andy J -- KL2TR000139/TR/NCATS NIH HHS/ -- P01AI112521/AI/NIAID NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- P30CA016520/CA/NCI NIH HHS/ -- P50 CA174523/CA/NCI NIH HHS/ -- P50CA174523/CA/NCI NIH HHS/ -- R01 AI105343/AI/NIAID NIH HHS/ -- R01 CA158186/CA/NCI NIH HHS/ -- R01 CA163739/CA/NCI NIH HHS/ -- R01AI105343/AI/NIAID NIH HHS/ -- R01CA158186/CA/NCI NIH HHS/ -- R01CA163739/CA/NCI NIH HHS/ -- R01CA172651/CA/NCI NIH HHS/ -- T32DK007066/DK/NIDDK NIH HHS/ -- U01AI095608/AI/NIAID NIH HHS/ -- U19 AI082630/AI/NIAID NIH HHS/ -- U19AI082630/AI/NIAID NIH HHS/ -- UL1RR024134/RR/NCRR NIH HHS/ -- England -- Nature. 2015 Apr 16;520(7547):373-7. doi: 10.1038/nature14292. Epub 2015 Mar 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Division of Biostatistics, Department of Public Health Sciences, University of Miami, Miami, Florida 33136, USA. ; 1] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [4] Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [4] Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25754329" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD274/*antagonists & inhibitors/metabolism ; CTLA-4 Antigen/*antagonists & inhibitors ; Cell Cycle Checkpoints/*drug effects ; Female ; Humans ; Melanoma/*drug therapy/*immunology/pathology/*radiotherapy ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Receptors, Antigen, T-Cell/drug effects/immunology/metabolism ; T-Lymphocytes/cytology/*drug effects/immunology/*radiation effects ; T-Lymphocytes, Regulatory/drug effects/immunology/radiation effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2015-01-17
    Description: CD4 T cells promote innate and adaptive immune responses, but how vaccine-elicited CD4 T cells contribute to immune protection remains unclear. We evaluated whether induction of virus-specific CD4 T cells by vaccination would protect mice against infection with chronic lymphocytic choriomeningitis virus (LCMV). Immunization with vaccines that selectively induced CD4 T cell responses resulted in catastrophic inflammation and mortality after challenge with a persistent strain of LCMV. Immunopathology required antigen-specific CD4 T cells and was associated with a cytokine storm, generalized inflammation, and multi-organ system failure. Virus-specific CD8 T cells or antibodies abrogated the pathology. These data demonstrate that vaccine-elicited CD4 T cells in the absence of effective antiviral immune responses can trigger lethal immunopathology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382081/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382081/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Penaloza-MacMaster, Pablo -- Barber, Daniel L -- Wherry, E John -- Provine, Nicholas M -- Teigler, Jeffrey E -- Parenteau, Lily -- Blackmore, Stephen -- Borducchi, Erica N -- Larocca, Rafael A -- Yates, Kathleen B -- Shen, Hao -- Haining, W Nicholas -- Sommerstein, Rami -- Pinschewer, Daniel D -- Ahmed, Rafi -- Barouch, Dan H -- AI007245/AI/NIAID NIH HHS/ -- AI030048/AI/NIAID NIH HHS/ -- AI07387/AI/NIAID NIH HHS/ -- AI078526/AI/NIAID NIH HHS/ -- AI096040/AI/NIAID NIH HHS/ -- P51 OD011132/OD/NIH HHS/ -- T32 AI007245/AI/NIAID NIH HHS/ -- U19 AI078526/AI/NIAID NIH HHS/ -- U19 AI096040/AI/NIAID NIH HHS/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 16;347(6219):278-82. doi: 10.1126/science.aaa2148.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. ; Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. ; Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. ; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. ; Department of Pathology and Immunology, WHO Collaborating Centre for Vaccine Immunology, University of Geneva, 1211 Geneva, Switzerland. ; Department of Pathology and Immunology, WHO Collaborating Centre for Vaccine Immunology, University of Geneva, 1211 Geneva, Switzerland. Department of Biomedicine-Haus Petersplatz, Division of Experimental Virology, University of Basel, 4009 Basel, Switzerland. ; Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA. ; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Ragon Institute of MGH, MIT, and Harvard, Boston, MA 02114, USA. dbarouch@bidmc.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25593185" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptive Immunity ; Animals ; Antibodies, Viral/immunology ; Antigens, Viral/immunology ; Arenaviridae Infections/*immunology/virology ; CD4-Positive T-Lymphocytes/*immunology ; CD8-Positive T-Lymphocytes/immunology ; Cytokines/blood ; Epitopes, T-Lymphocyte/immunology ; Immune System Diseases/*etiology/immunology/pathology ; Immunologic Memory ; Inflammation/*etiology/immunology/pathology ; Lymphocytic choriomeningitis virus/*immunology/physiology ; Mice, Inbred C57BL ; Multiple Organ Failure/etiology ; Vaccination ; Viral Load ; Viral Vaccines/*adverse effects/*immunology ; Virus Replication
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2016-10-12
    Description: The T-cell receptor (TCR) is required for maturation and function of regulatory T cells (Tregs), but the ligand specificities of Tregs outside the context of transgenic TCRs are largely unknown. Using peptide–MHC tetramers, we isolated rare specific Foxp3+ cells directly ex vivo from adult peripheral blood and defined their frequency...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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