Heat Shock Protein-90 Inhibition Alters Activation of Pancreatic Stellate Cells and Enhances the Efficacy of PD-1 Blockade in Pancreatic Cancer

• Type of Material: Article
• Authors: Yuchen Zhang, Emory University; Michael B. Ware, Emory University; Mohammad Y. Zaidi, Emory University; Amanda N. Ruggieri, Emory University; Brian Olson, Emory University; Hannah Komar, Emory University; Matthew R. Farren, Emory University; Purnachandra Ganji, Emory University; Chao Zhang, Emory University; Zhengjia Chen, Emory University; Juan Sarmiento, Emory University; Rafi Ahmed, Emory University; Shishir Maithel, Emory University; Bassel El-Rayes, Emory University; Gregory Lesinski, Emory University
• Language: English
• Date: 2021-01-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 by the American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/1535-7163.MCT-19-0911
• Title of Journal or Parent Work: Molecular Cancer Therapeutics
• Volume: 20
• Issue: 1
• Start Page: 150
• End Page: 160
• Grant/Funding Information: Supported by NIH grant 1R01CA228406-01A1 and P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; Research reported in this publication was supported in part by the Biostatistics and Bioinformatics, Integrated Cell Imaging, Pathology Shared Resources of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292
• Keywords: Target; Promote; Life Sciences & Biomedicine; Oncology; Stroma; Fibroblasts; Suppressor cells; Science & Technology; Liver; Tumor; HSP90 inhibitor; Growth; Therapy
• Research Categories: Health Sciences, Oncology; Health Sciences, Radiology; Health Sciences, Immunology; Biology, Cell

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a prominent fibrotic stroma, which is a result of interactions between tumor, immune and pancreatic stellate cells (PSC), or cancer-associated fibroblasts (CAF). Targeting inflammatory pathways present within the stroma may improve access of effector immune cells to PDAC and response to immunotherapy. Heat shock protein-90 (Hsp90) is a chaperone protein and a versatile target in pancreatic cancer. Hsp90 regulates a diverse array of cellular processes of relevance to both the tumor and the immune system. However, to date the role of Hsp90 in PSC/CAF has not been explored in detail. We hypothesized that Hsp90 inhibition would limit inflammatory signals, thereby reprogramming the PDAC tumor microenvironment to enhance sensitivity to PD-1 blockade. Treatment of immortalized and primary patient PSC/CAF with the Hsp90 inhibitor XL888 decreased IL6, a key cytokine that orchestrates immune changes in PDAC at the transcript and protein level in vitro. XL888 directly limited PSC/CAF growth and reduced Jak/STAT and MAPK signaling intermediates and alpha-SMA expression as determined via immunoblot. Combined therapy with XL888 and anti–PD-1 was efficacious in C57BL/6 mice bearing syngeneic subcutaneous (Panc02) or orthotopic (KPC-Luc) tumors. Tumors from mice treated with both XL888 and anti–PD-1 had a significantly increased CD8þ and CD4þ T-cell infiltrate and a unique transcriptional profile characterized by upregulation of genes associated with immune response and chemotaxis. These data demonstrate that Hsp90 inhibition directly affects PSC/CAF in vitro and enhances the efficacy of anti–PD-1 blockade in vivo.