NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma

DOI PDF 被引用文献3件
  • Donnele Daley
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1
  • Vishnu R. Mani
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1
  • Navyatha Mohan
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1
  • Neha Akkad
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1
  • Gautam S.D. Balasubramania Pandian
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1
  • Shivraj Savadkar
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1
  • Ki Buom Lee
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1
  • Alejandro Torres-Hernandez
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1
  • Berk Aykut
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1
  • Brian Diskin
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1
  • Wei Wang
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1
  • Mohammad S. Farooq
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1
  • Arif I. Mahmud
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1
  • Gregor Werba
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1
  • Eduardo J. Morales
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1
  • Sarah Lall
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1
  • Benjamin J. Wadowski
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1
  • Amanda G. Rubin
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1
  • Matthew E. Berman
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1
  • Rajkishen Narayanan
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1
  • Mautin Hundeyin
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1
  • George Miller
    S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016 1

説明

<jats:p>The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance, which enables disease to progress unabated by adaptive immunity. However, the drivers of this tolerogenic program are incompletely defined. In this study, we found that NLRP3 promotes expansion of immune-suppressive macrophages in PDA. NLRP3 signaling in macrophages drives the differentiation of CD4+ T cells into tumor-promoting T helper type 2 cell (Th2 cell), Th17 cell, and regulatory T cell populations while suppressing Th1 cell polarization and cytotoxic CD8+ T cell activation. The suppressive effects of NLRP3 signaling were IL-10 dependent. Pharmacological inhibition or deletion of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD complex), or caspase-1 protected against PDA and was associated with immunogenic reprogramming of innate and adaptive immunity within the TME. Similarly, transfer of PDA-entrained macrophages or T cells from NLRP3−/− hosts was protective. These data suggest that targeting NLRP3 holds the promise for the immunotherapy of PDA.</jats:p>

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