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

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 CD8 þ and CD4 þ 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.

Immune checkpoint inhibition for pancreatic ductal adenocarcinoma: limitations and prospects: a systematic review

“…The reason for this is not known and may be related to drug dose [ 115 ]. Growth of TAMs/cancer-associated fibroblasts (CAFs) can be directly inhibited by blocking the PAK1 [ 116 ] pathway or using xl888 (a heat shock protein 90 inhibitor) [ 117 ]. Thus, these two novel therapeutic methods targeting PSCs not only improve T-cell proliferation and infiltration, but also significantly improve the efficacy of ICIs as adjuvants.…”

Prognostic value and potential molecular mechanism of the like-Sm gene family in early-stage pancreatic ductal adenocarcinoma

“…However, PDAC has a rich fibrotic stroma, and it lack lacks antigen-experienced T effector cells, hence immunotherapy is not effective for pancreatic cancer ( 60 ). The latest research shows that heat shock protein-90 can inhibit PSC/CAF in vitro and enhance the anti-PD-1 blocking effect in vivo ( 61 ). Additionally, in mouse experiments, combining anti-PD-1 and vaccine can have good anti-tumor activity; anti-CD137 agonist antibody combined with anti-PD-1 and vaccine significantly improved the survival time of the mouse PDAC model, highlighting a potential treatment option ( 62 ).…”

The Role of Stellate Cells in Pancreatic Ductal Adenocarcinoma: Targeting Perspectives

“…ICG-001, a cAMP-responsive element binding (CREB)-binding protein (CBP)/ β -catenin antagonist, was shown to suppress the activation of PSCs and PSC-induced migration of PCCs ( 169 ). Zhang et al reported that a heat shock protein 90 (Hsp90) inhibitor, XL888, reduced PSC activation, and enhanced the efficacy of anti-programmed cell death protein 1 (PD-1) blockade in tumor-bearing mice ( 170 ). Attempts are also made in reprogramming PSCs by miRNA, a potential therapeutic target ( 206 ).…”