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  • Aleynick, MarkGraduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA (author)

Pattern recognition receptor agonists in pathogen vaccines mediate antitumor T-cell cross-priming

  • Article/chapterEnglish2023

Publisher, publication year, extent ...

  • BMJ Publishing Group Ltd,2023
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:liu-199615
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-199615URI
  • https://doi.org/10.1136/jitc-2023-007198DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Background Cancer immunotherapies are generallyeffective in patients whose tumors contain a prioriprimed T-cells reactive to tumor antigens (TA). Oneapproach to prime TA-reactive T-cells is to administerimmunostimulatory molecules, cells, or pathogens directlyto the tumor site, that is, in situ vaccination (ISV). Werecently described an ISV using Flt3L to expand and recruitdendritic cells (DC), radiotherapy to load DC with TA, andpattern recognition receptor agonists (PRRa) to activateTA-loaded DC. While ISV trials using synthetic PRRa haveyielded systemic tumor regressions, the optimal method toactivate DCs is unknown.Methods To discover optimal DC activators and increaseaccess to clinical grade reagents, we assessed whetherviral or bacterial components found in common pathogenvaccines are an effective source of natural PRRa(naPRRa). Using deep profiling (155-metric) of naPRRaimmunomodulatory effects and gene editing of specificPRR, we defined specific signatures and molecularmechanisms by which naPRRa potentiate T-cell priming.Results We observed that vaccine naPRRa can be evenmore potent in activating Flt3L-expanded murine andhuman DCs than synthetic PRRa, promoting cross-primingof TA-reactive T-cells. We developed a mechanisticallydiverse naPRRa combination (BCG, PedvaxHIB, Rabies)and noted more potent T-cell cross-priming than withany single naPRRa. The naPRRa triplet—as part of Flt3Lprimed ISV—induced greater intratumoral CD8 T-cellinfiltration, T-cells reactive to a newly defined tumorousneoantigen, durable tumor regressions.Conclusions This work provides rationale for thetranslation of pathogen vaccines as FDA-approved clinicalgrade DC activators which could be exploited as immunestimulants for early phase trials.

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Added entries (persons, corporate bodies, meetings, titles ...)

  • Svensson-Arvelund, Judit,1982-Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA(Swepub:liu)judsv82 (author)
  • Pantsulaia, GvantsaMarc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA (author)
  • Kim, KristyMarc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA (author)
  • Rose, Samuel A.Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, USA (author)
  • Upadhyay, RanjanGraduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA (author)
  • Yellin, MichaelCelldex Therapeutics Inc, Hampton, New Jersey, USA (author)
  • Marsh, HenryCelldex Therapeutics Inc, Hampton, New Jersey, USA (author)
  • Oreper, DanielGenentech Inc, South San Francisco, California, USA (author)
  • Jhunjhunwala, SuchitGenentech Inc, South San Francisco, California, USA (author)
  • Moussion, Christine CarineGenentech Inc, South San Francisco, California, USA (author)
  • Merad, MiriamMarc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA (author)
  • Brown, Brian D.Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA (author)
  • Brody, Joshua D.Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA (author)
  • Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USAMarc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA (creator_code:org_t)

Related titles

  • In:Journal for ImmunoTherapy of Cancer: BMJ Publishing Group Ltd11:72051-1426

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