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Pancreatic Ductal Adenocarcinoma Cells Regulate NLRP3 Activation to Generate a Tolerogenic Microenvironment
Defining feature of pancreatic ductal adenocarcinoma (PDAC) that participates in the high mortality rate and drug resistance is the immune-tolerant microenvironment which enables tumors to progress unabated by adaptive immunity. In this study, we report that PDAC cells release CSF-1 to induce nucleo...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10510589/ https://www.ncbi.nlm.nih.gov/pubmed/37772994 http://dx.doi.org/10.1158/2767-9764.CRC-23-0065 |
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author | Amo-Aparicio, Jesus Dominguez, Adrian Atif, Shaikh M. Dinarello, Alberto Azam, Tania Alula, Kibrom M. Piper, Miles Lieu, Christopher H. Lentz, Robert W. Leal, Alexis D. Bagby, Stacey M. Messersmith, Wells A. Karam, Sana D. Dinarello, Charles A. Pitts, Todd M. Marchetti, Carlo |
author_facet | Amo-Aparicio, Jesus Dominguez, Adrian Atif, Shaikh M. Dinarello, Alberto Azam, Tania Alula, Kibrom M. Piper, Miles Lieu, Christopher H. Lentz, Robert W. Leal, Alexis D. Bagby, Stacey M. Messersmith, Wells A. Karam, Sana D. Dinarello, Charles A. Pitts, Todd M. Marchetti, Carlo |
author_sort | Amo-Aparicio, Jesus |
collection | PubMed |
description | Defining feature of pancreatic ductal adenocarcinoma (PDAC) that participates in the high mortality rate and drug resistance is the immune-tolerant microenvironment which enables tumors to progress unabated by adaptive immunity. In this study, we report that PDAC cells release CSF-1 to induce nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) activation in myeloid cells. Increased NLRP3 expression was found in the pancreas of patients with PDAC when compared with normal pancreas which correlated with the formation of the NLRP3 inflammasome. Using human primary cells and an orthotopic PDAC mouse model, we show that NLRP3 activation is responsible for the maturation and release of the inflammatory cytokine IL1β which selectively drives Th2-type inflammation via COX2/PGE2 induction. As a result of this inflammation, primary tumors were characterized by reduced cytotoxic CD8(+) T-cell activation and increased tumor expansion. Genetic deletion and pharmacologic inhibition of NLRP3 enabled the development of Th1 immunity, increased intratumoral levels of IL2, CD8(+) T cell–mediated tumor suppression, and ultimately limited tumor growth. In addition, we observed that NLRP3 inhibition in combination with gemcitabine significantly increased the efficacy of the chemotherapy. In conclusion, this study provides a mechanism by which tumor-mediated NLRP3 activation exploits a distinct adaptive immunity response that facilitates tumor escape and progression. Considering the ability to block NLRP3 activity with safe and small orally active molecules, this protein represents a new promising target to improve the limited therapeutic options in PDAC. SIGNIFICANT: This study provides novel molecular insights on how PDAC cells exploit NLRP3 activation to suppress CD8 T-cell activation. From a translational perspective, we demonstrate that the combination of gemcitabine with the orally active NLRP3 inhibitor OLT1177 increases the efficacy of monotherapy. |
format | Online Article Text |
id | pubmed-10510589 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-105105892023-09-21 Pancreatic Ductal Adenocarcinoma Cells Regulate NLRP3 Activation to Generate a Tolerogenic Microenvironment Amo-Aparicio, Jesus Dominguez, Adrian Atif, Shaikh M. Dinarello, Alberto Azam, Tania Alula, Kibrom M. Piper, Miles Lieu, Christopher H. Lentz, Robert W. Leal, Alexis D. Bagby, Stacey M. Messersmith, Wells A. Karam, Sana D. Dinarello, Charles A. Pitts, Todd M. Marchetti, Carlo Cancer Res Commun Research Article Defining feature of pancreatic ductal adenocarcinoma (PDAC) that participates in the high mortality rate and drug resistance is the immune-tolerant microenvironment which enables tumors to progress unabated by adaptive immunity. In this study, we report that PDAC cells release CSF-1 to induce nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) activation in myeloid cells. Increased NLRP3 expression was found in the pancreas of patients with PDAC when compared with normal pancreas which correlated with the formation of the NLRP3 inflammasome. Using human primary cells and an orthotopic PDAC mouse model, we show that NLRP3 activation is responsible for the maturation and release of the inflammatory cytokine IL1β which selectively drives Th2-type inflammation via COX2/PGE2 induction. As a result of this inflammation, primary tumors were characterized by reduced cytotoxic CD8(+) T-cell activation and increased tumor expansion. Genetic deletion and pharmacologic inhibition of NLRP3 enabled the development of Th1 immunity, increased intratumoral levels of IL2, CD8(+) T cell–mediated tumor suppression, and ultimately limited tumor growth. In addition, we observed that NLRP3 inhibition in combination with gemcitabine significantly increased the efficacy of the chemotherapy. In conclusion, this study provides a mechanism by which tumor-mediated NLRP3 activation exploits a distinct adaptive immunity response that facilitates tumor escape and progression. Considering the ability to block NLRP3 activity with safe and small orally active molecules, this protein represents a new promising target to improve the limited therapeutic options in PDAC. SIGNIFICANT: This study provides novel molecular insights on how PDAC cells exploit NLRP3 activation to suppress CD8 T-cell activation. From a translational perspective, we demonstrate that the combination of gemcitabine with the orally active NLRP3 inhibitor OLT1177 increases the efficacy of monotherapy. American Association for Cancer Research 2023-09-20 /pmc/articles/PMC10510589/ /pubmed/37772994 http://dx.doi.org/10.1158/2767-9764.CRC-23-0065 Text en © 2023 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by/4.0/This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license. |
spellingShingle | Research Article Amo-Aparicio, Jesus Dominguez, Adrian Atif, Shaikh M. Dinarello, Alberto Azam, Tania Alula, Kibrom M. Piper, Miles Lieu, Christopher H. Lentz, Robert W. Leal, Alexis D. Bagby, Stacey M. Messersmith, Wells A. Karam, Sana D. Dinarello, Charles A. Pitts, Todd M. Marchetti, Carlo Pancreatic Ductal Adenocarcinoma Cells Regulate NLRP3 Activation to Generate a Tolerogenic Microenvironment |
title | Pancreatic Ductal Adenocarcinoma Cells Regulate NLRP3 Activation to Generate a Tolerogenic Microenvironment |
title_full | Pancreatic Ductal Adenocarcinoma Cells Regulate NLRP3 Activation to Generate a Tolerogenic Microenvironment |
title_fullStr | Pancreatic Ductal Adenocarcinoma Cells Regulate NLRP3 Activation to Generate a Tolerogenic Microenvironment |
title_full_unstemmed | Pancreatic Ductal Adenocarcinoma Cells Regulate NLRP3 Activation to Generate a Tolerogenic Microenvironment |
title_short | Pancreatic Ductal Adenocarcinoma Cells Regulate NLRP3 Activation to Generate a Tolerogenic Microenvironment |
title_sort | pancreatic ductal adenocarcinoma cells regulate nlrp3 activation to generate a tolerogenic microenvironment |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10510589/ https://www.ncbi.nlm.nih.gov/pubmed/37772994 http://dx.doi.org/10.1158/2767-9764.CRC-23-0065 |
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