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

Publication ,  Journal Article
Daley, D; Mani, VR; Mohan, N; Akkad, N; Pandian, GSDB; Savadkar, S; Lee, KB; Torres-Hernandez, A; Aykut, B; Diskin, B; Wang, W; Farooq, MS ...
Published in: The Journal of experimental medicine
June 2017

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.

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Published In

The Journal of experimental medicine

DOI

EISSN

1540-9538

ISSN

0022-1007

Publication Date

June 2017

Volume

214

Issue

6

Start / End Page

1711 / 1724

Related Subject Headings

  • Tumor Microenvironment
  • T-Lymphocytes
  • Signal Transduction
  • Pancreatic Stellate Cells
  • Pancreatic Neoplasms
  • Nod2 Signaling Adaptor Protein
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Mice, Inbred C57BL
  • Macrophages
  • Immunosuppression Therapy
 

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Daley, D., Mani, V. R., Mohan, N., Akkad, N., Pandian, G. S. D. B., Savadkar, S., … Miller, G. (2017). NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma. The Journal of Experimental Medicine, 214(6), 1711–1724. https://doi.org/10.1084/jem.20161707
Daley, Donnele, Vishnu R. Mani, Navyatha Mohan, Neha Akkad, Gautam SD Balasubramania Pandian, Shivraj Savadkar, Ki Buom Lee, et al. “NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma.The Journal of Experimental Medicine 214, no. 6 (June 2017): 1711–24. https://doi.org/10.1084/jem.20161707.
Daley D, Mani VR, Mohan N, Akkad N, Pandian GSDB, Savadkar S, et al. NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma. The Journal of experimental medicine. 2017 Jun;214(6):1711–24.
Daley, Donnele, et al. “NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma.The Journal of Experimental Medicine, vol. 214, no. 6, June 2017, pp. 1711–24. Epmc, doi:10.1084/jem.20161707.
Daley D, Mani VR, Mohan N, Akkad N, Pandian GSDB, Savadkar S, Lee KB, Torres-Hernandez A, Aykut B, Diskin B, Wang W, Farooq MS, Mahmud AI, Werba G, Morales EJ, Lall S, Wadowski BJ, Rubin AG, Berman ME, Narayanan R, Hundeyin M, Miller G. NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma. The Journal of experimental medicine. 2017 Jun;214(6):1711–1724.

Published In

The Journal of experimental medicine

DOI

EISSN

1540-9538

ISSN

0022-1007

Publication Date

June 2017

Volume

214

Issue

6

Start / End Page

1711 / 1724

Related Subject Headings

  • Tumor Microenvironment
  • T-Lymphocytes
  • Signal Transduction
  • Pancreatic Stellate Cells
  • Pancreatic Neoplasms
  • Nod2 Signaling Adaptor Protein
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Mice, Inbred C57BL
  • Macrophages
  • Immunosuppression Therapy