@article{6d0b338dc940452788e4d6249b8877b4,
title = "IRAK4 Signaling Drives Resistance to Checkpoint Immunotherapy in Pancreatic Ductal Adenocarcinoma",
abstract = "Background & Aims: Checkpoint immunotherapy is largely ineffective in pancreatic ductal adenocarcinoma (PDAC). The innate immune nuclear factor (NF)-κB pathway promotes PDAC cell survival and stromal fibrosis, and is driven by Interleukin-1 Receptor Associated Kinase-4 (IRAK4), but its impact on tumor immunity has not been directly investigated. Methods: We interrogated The Cancer Genome Atlas data to identify the correlation between NF-κB and T cell signature, and a PDAC tissue microarray (TMA) to correlate IRAK4 activity with CD8+ T cell abundance. We performed RNA sequencing (RNA-seq) on IRAK4-deleted PDAC cells, and single-cell RNA-seq on autochthonous KPC (p48-Cre/TP53f/f/LSL-KRASG12D) mice treated with an IRAK4 inhibitor. We generated conditional IRAK4-deleted KPC mice and complementarily used IRAK4 inhibitors to determine the impact of IRAK4 on T cell immunity. Results: We found positive correlation between NF-κB activity, IRAK4 and T cell exhaustion from The Cancer Genome Atlas. We observed inverse correlation between phosphorylated IRAK4 and CD8+ T cell abundance in a PDAC tissue microarray. Loss of IRAK4 abrogates NF-κB activity, several immunosuppressive factors, checkpoint ligands, and hyaluronan synthase 2, all of which drive T cell dysfunction. Accordingly, conditional deletion or pharmacologic inhibition of IRAK4 markedly decreased tumor desmoplasia and increased the abundance and activity of infiltrative CD4+ and CD8+ T cells in KPC tumors. Single-cell RNA-seq showed myeloid and fibroblast reprogramming toward acute inflammatory responses following IRAK4 inhibition. These changes set the stage for successful combination of IRAK4 inhibitors with checkpoint immunotherapy, resulting in excellent tumor control and markedly prolonged survival of KPC mice. Conclusion: IRAK4 drives T cell dysfunction in PDAC and is a novel, promising immunotherapeutic target.",
keywords = "CA-4948, HAS2, NF-κB, PD-L1, T cell exhaustion",
author = "Somani, {Vikas K.} and Daoxiang Zhang and Dodhiawala, {Paarth B.} and Lander, {Varintra E.} and Xiuting Liu and Kang, {Liang I.} and Chen, {Hung Po} and Knolhoff, {Brett L.} and Lin Li and Grierson, {Patrick M.} and Ruzinova, {Marianna B.} and DeNardo, {David G.} and Lim, {Kian Huat}",
note = "Funding Information: We would like to acknowledge support from the Washington University DDRCC (NIDDK P30 DK052574) and Genome Technology Access Center (NCI P30 CA91842) for help with genomic analysis. Funding Information: Funding Supported by the following: National Institutes of Health (NIH) R37CA219697–01, NIH 1P50CA196510–01A1, American Cancer Society (RSG-17–203–01-TBG), Alvin J. Siteman Cancer Center Siteman Investment Program (supported by Barnard Trust and The Foundation for Barnes-Jewish Hospital) and generous gift from Samuel R. Nussbaum, MD, and family. Funding Information: We would like to acknowledge support from the Washington University DDRCC (NIDDK P30 DK052574) and Genome Technology Access Center (NCI P30 CA91842) for help with genomic analysis. All data, analytic methods, and study materials will be made available to other researchers on request. Order of Authors (with Contributor Roles):, Vikas Somani, PhD (Data curation: Equal; Formal analysis: Equal; Investigation: Equal; Methodology: Equal; Validation: Equal; Writing – original draft: Lead), Daoxiang Zhang, PhD (Data curation: Equal; Formal analysis: Equal; Investigation: Equal; Methodology: Equal; Validation: Supporting), Paarth B. Dodhiawala, BS (Data curation: Equal; Formal analysis: Equal; Investigation: Equal), Varintra Krisnawan, BS (Data curation: Equal; Formal analysis: Equal; Investigation: Supporting; Software: Lead), Xiuting Liu, PhD (Formal analysis: Supporting; Investigation: Supporting), Liang-I Kang, MD, PhD (Formal analysis: Supporting; Investigation: Supporting), Hung-Po Chen, PhD (Data curation: Supporting; Investigation: Supporting), Brett L. Knolhoff, BS (Investigation: Supporting), Lin Li, Ms. S (Investigation: Supporting), Patrick M. Grierson, MD, PhD (Investigation: Supporting; Methodology: Supporting), Mariana B. Ruzinova, MD, PhD (Formal analysis: Equal; Investigation: Equal; Resources: Equal; Validation: Lead), David G. DeNardo, PhD (Formal analysis: Equal; Validation: Equal; Writing – original draft: Supporting), Kian-Huat Lim, MD, PhD (Conceptualization: Lead; Formal analysis: Supporting; Funding acquisition: Lead; Investigation: Supporting; Project administration: Lead; Resources: Lead; Supervision: Lead; Validation: Lead; Writing – original draft: Lead) Funding Supported by the following: National Institutes of Health (NIH) R37CA219697–01, NIH 1P50CA196510–01A1, American Cancer Society (RSG-17–203–01-TBG), Alvin J. Siteman Cancer Center Siteman Investment Program (supported by Barnard Trust and The Foundation for Barnes-Jewish Hospital) and generous gift from Samuel R. Nussbaum, MD, and family. Publisher Copyright: {\textcopyright} 2022 AGA Institute",
year = "2022",
month = jun,
doi = "10.1053/j.gastro.2022.02.035",
language = "English",
volume = "162",
pages = "2047--2062",
journal = "Gastroenterology",
issn = "0016-5085",
number = "7",
}