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

Donnele Daley; Vishnu R. Mani; Navyatha Mohan; Neha Akkad; Gautam S.D. Balasubramania Pandian; Shivraj Savadkar; Ki Buom Lee; Alejandro Torres-Hernandez; Berk Aykut; Brian Diskin; Wei Wang; Mohammad S. Farooq; Arif I. Mahmud; Gregor Werba; Eduardo J. Morales; Sarah Lall; Benjamin J. Wadowski; Amanda G. Rubin; Matthew E. Berman; Rajkishen Narayanan; Mautin Hundeyin; George Miller

doi:10.1084/jem.20161707

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

Donnele Daley, Vishnu R. Mani, Navyatha Mohan, Neha Akkad, Gautam S.D. Balasubramania Pandian, Shivraj Savadkar, Ki Buom Lee, Alejandro Torres-Hernandez, Berk Aykut, Brian Diskin, Wei Wang, Mohammad S. Farooq, Arif I. Mahmud, Gregor Werba, Eduardo J. Morales, Sarah Lall, Benjamin J. Wadowski, Amanda G. Rubin, Matthew E. Berman, Rajkishen NarayananMautin Hundeyin, George Miller

Research output: Contribution to journal › Article › peer-review

217 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	1711-1724
Number of pages	14
Journal	Journal of Experimental Medicine
Volume	214
Issue number	6
DOIs	https://doi.org/10.1084/jem.20161707
State	Published - Jun 1 2017

Bibliographical note

Publisher Copyright:
© 2017 Daley et al.

Funding

This work was supported by National Institutes of Health grants (CA168611, CA155649, and CA206105 to G. Miller), the Department of Defense Peer Reviewed Medical Research Program (G. Miller), the Lustgarten Foundation (G. Miller), the American Association for Cancer Research Pancreatic Cancer Action Network (G. Miller), the Hirshberg Foundation for Pancreatic Cancer Research (G. Miller), and the Irene and Bernard Schwartz Fellowship in Gastrointestinal Oncology (D. Daley).

Funders	Funder number
American Association for Cancer Research Pancreatic Cancer Action Network
National Institutes of Health (NIH)	CA155649, CA206105
National Institutes of Health (NIH)
U.S. Department of Defense
National Childhood Cancer Registry – National Cancer Institute	R01CA168611
National Childhood Cancer Registry – National Cancer Institute
Hirshberg Foundation for Pancreatic Cancer Research
Lustgarten Foundation

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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Daley, D., Mani, V. R., Mohan, N., Akkad, N., Balasubramania Pandian, G. S. D., Savadkar, S., Lee, K. B., Torres-Hernandez, A., Aykut, B., Diskin, B., Wang, W., Farooq, M. S., Mahmud, A. I., Werba, G., Morales, E. J., Lall, S., Wadowski, B. J., Rubin, A. G., Berman, M. E., ... Miller, G. (2017). NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma. Journal of Experimental Medicine, 214(6), 1711-1724. https://doi.org/10.1084/jem.20161707

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title = "NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma",

abstract = "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.",

author = "Donnele Daley and Mani, \{Vishnu R.\} and Navyatha Mohan and Neha Akkad and \{Balasubramania Pandian\}, \{Gautam S.D.\} and Shivraj Savadkar and Lee, \{Ki Buom\} and Alejandro Torres-Hernandez and Berk Aykut and Brian Diskin and Wei Wang and Farooq, \{Mohammad S.\} and Mahmud, \{Arif I.\} and Gregor Werba and Morales, \{Eduardo J.\} and Sarah Lall and Wadowski, \{Benjamin J.\} and Rubin, \{Amanda G.\} and Berman, \{Matthew E.\} and Rajkishen Narayanan and Mautin Hundeyin and George Miller",

note = "Publisher Copyright: {\textcopyright} 2017 Daley et al.",

year = "2017",

month = jun,

day = "1",

doi = "10.1084/jem.20161707",

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Daley, D, Mani, VR, Mohan, N, Akkad, N, Balasubramania Pandian, GSD, 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 2017, 'NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma', Journal of Experimental Medicine, vol. 214, no. 6, pp. 1711-1724. https://doi.org/10.1084/jem.20161707

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AU - Daley, Donnele

AU - Mani, Vishnu R.

AU - Mohan, Navyatha

AU - Akkad, Neha

AU - Balasubramania Pandian, Gautam S.D.

AU - Savadkar, Shivraj

AU - Lee, Ki Buom

AU - Torres-Hernandez, Alejandro

AU - Aykut, Berk

AU - Diskin, Brian

AU - Wang, Wei

AU - Farooq, Mohammad S.

AU - Mahmud, Arif I.

AU - Werba, Gregor

AU - Morales, Eduardo J.

AU - Lall, Sarah

AU - Wadowski, Benjamin J.

AU - Rubin, Amanda G.

AU - Berman, Matthew E.

AU - Narayanan, Rajkishen

AU - Hundeyin, Mautin

AU - Miller, George

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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.

AB - 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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JF - Journal of Experimental Medicine

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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