TY - JOUR
T1 - NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma
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
N1 - Publisher Copyright:
© 2017 Daley et al.
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.
UR - http://www.scopus.com/inward/record.url?scp=85021854722&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85021854722&partnerID=8YFLogxK
U2 - 10.1084/jem.20161707
DO - 10.1084/jem.20161707
M3 - Article
C2 - 28442553
AN - SCOPUS:85021854722
SN - 0022-1007
VL - 214
SP - 1711
EP - 1724
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 6
ER -