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FIGURE 2 from Pancreatic Ductal Adenocarcinoma Cells Regulate NLRP3 Activation to Generate a Tolerogenic Microenvironment

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posted on 2023-09-20, 14:20 authored by Jesus Amo-Aparicio, Adrian Dominguez, Shaikh M. Atif, Alberto Dinarello, Tania Azam, Kibrom M. Alula, Miles Piper, Christopher H. Lieu, Robert W. Lentz, Alexis D. Leal, Stacey M. Bagby, Wells A. Messersmith, Sana D. Karam, Charles A. Dinarello, Todd M. Pitts, Carlo Marchetti

PDAC paracrine activity mediates NLRP3 activation. A, IL1β and IL18 secretion from freshly isolated PBMCs from healthy donors (n = 6) following stimulation with PDAC-conditioned media obtained from AsPC-1, MiaPaCa-2, and Panc-1 cells. B, IL1β and IL18 secretion from parenteral (WT) and NLRP3 deficient (NLRP3−/−) THP-1 cells following stimulation with PDAC-conditioned media obtained from Panc-1 cells (n = 3). C, IL1β and IL18 secretion from THP-1 cells following stimulation with PDAC-conditioned media obtained from Panc-1 cells in presence of the NLRP3 inhibitors OLT1177 (OLT) and MCC950 (MCC; n = 3). Cytokine levels were measured by specific ELISA kits. Data expressed as mean ± SEM; ****, P < 0.0001; **, P < 0.01; *, P < 0.05.

Funding

Wings of hope for pancreatic cancer research

American Cancer Society (ACS)

CU | Cancer Center, University of Colorado (CU Cancer Center)

Amini Pancreatic Cancer Research Fund

HHS | NIH | National Cancer Institute (NCI)

Gina Guy Chair in Pancreatic Cancer Research

HHS | National Institutes of Health (NIH)

History

ARTICLE ABSTRACT

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.