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

Aleynick, Mark (författare)
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, USA
Svensson-Arvelund, Judit, 1982- (författare)
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
Pantsulaia, Gvantsa (författare)
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
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Kim, Kristy (författare)
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
Rose, Samuel A. (författare)
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
Upadhyay, Ranjan (författare)
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, USA
Yellin, Michael (författare)
Celldex Therapeutics Inc, Hampton, New Jersey, USA
Marsh, Henry (författare)
Celldex Therapeutics Inc, Hampton, New Jersey, USA
Oreper, Daniel (författare)
Genentech Inc, South San Francisco, California, USA
Jhunjhunwala, Suchit (författare)
Genentech Inc, South San Francisco, California, USA
Moussion, Christine Carine (författare)
Genentech Inc, South San Francisco, California, USA
Merad, Miriam (författare)
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA
Brown, Brian D. (författare)
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA
Brody, Joshua D. (författare)
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
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 (creator_code:org_t)
BMJ Publishing Group Ltd, 2023
2023
Engelska.
Ingår i: Journal for ImmunoTherapy of Cancer. - : BMJ Publishing Group Ltd. - 2051-1426. ; 11:7
Relaterad länk:
https://doi.org/10.1...
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https://urn.kb.se/re...
https://doi.org/10.1...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Immunology in the medical area (hsv//eng)

Nyckelord

Adjuvants
Immunologic; Antigen Presentation; Dendritic Cells; Immunotherapy
Active; Vaccination

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