TAK1 Promotes an Immunosuppressive Tumor Microenvironment through Cancer-Associated Fibroblast Phenotypic Conversion in Pancreatic Ductal Adenocarcinoma

• Published in: Clinical cancer research 2024-11, Vol.30 (22), p.5138-5153
• Main Authors: Sheng, Nan, Shindo, Koji, Ohuchida, Kenoki, Shinkawa, Tomohiko, Zhang, Bo, Feng, Haimin, Yamamoto, Takeo, Moriyama, Taiki, Ikenaga, Naoki, Nakata, Kohei, Oda, Yoshinao, Nakamura, Masafumi
• Format: Article
• Language: English
• Subjects: Animals; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - immunology; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Cell Proliferation; Gastrointestinal Cancers; Gene Expression Regulation, Neoplastic; Humans; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - metabolism; Mice; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Phenotype; Signal Transduction; Translational Cancer Mechanisms and Therapy; Tumor Microenvironment; Tumor Microenvironment - immunology
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-24-1004

We aim to clarify the precise function of TGFβ1-activated kinase 1 (TAK1) in cancer-associated fibroblasts (CAF) within human pancreatic ductal adenocarcinoma (PDAC) by investigating its role in cytokine-mediated signaling pathways. The expression of TAK1 in pancreatic cancer was confirmed by The Cancer Genome Atlas data and human pancreatic cancer specimens. CAFs from freshly resected PDAC specimens were cultured and used in a three-dimensional model for direct and indirect coculture with PDAC tumors to investigate TAK1 function. Additionally, organoids from [LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre (KPC)] mice were mixed with CAFs and injected subcutaneously into C57BL/6 mice to explore in vivo functional interactions of TAK1. The Cancer Genome Atlas data revealed significant upregulation of TAK1 in PDAC, associating with a positive correlation with the T-cell exhaustion signature. Knockdown of TAK1 in CAFs decreased the inflammatory CAF signature and increased the myofibroblastic CAF signature both in vitro and in vivo. The absence of TAK1 hindered CAF proliferation, blocked several inflammatory factors via multiple pathways associated with immunosuppression, and hindered epithelial-mesenchymal transition and outgrowth in vitro in spheroid cocultures with PDAC cells. Additionally, TAK1 inhibitor restrained tumor growth, increased CD4+ and CD8+ T-cell abundance, and reduced immunosuppressive cells present in vivo. Blocking the TAK1+ CAF phenotype leads to the conversion of protumorigenic CAFs to antitumorigenic CAFs. This highlights TAK1 as a potential therapeutic target, particularly in CAFs, and represents a novel avenue for combined immunotherapy in PDAC.