Depletion of adipose stroma-like cancer-associated fibroblasts potentiates pancreatic cancer immunotherapy

• Published in: Cancer research communications 2024-12
• Main Authors: Rupert, Joseph, Daquinag, Alexes, Yu, Yongmei, Dai, Yulin, Zhao, Zhongming, Kolonin, Mikhail G
• Format: Article
• Language: English
• ISSN: 2767-9764; 2767-9764
• DOI: 10.1158/2767-9764.CRC-24-0298

Immune checkpoint blockade therapy, transformative in some cancer types, has remained ineffective for patients with pancreatic cancer. The effects of sub-populations of cancer-associated fibroblasts (CAFs) on cancer progression and therapy resistance are incompletely understood. Here, the roles of CAFs expressing platelet-derived growth factor receptor beta (Pdgfrb) and of CAFs expressing markers of adipose stromal cells (ASCs) were analyzed in mice with pancreatic ductal adenocarcinoma. Ablation of Pdgfrb+ cells resulted in suppression of primary pancreatic tumor growth, reduction of extracellular matrix (ECM) deposition, and increased cancer cell metastasis to the liver. A peptide D-CAN, which induces apoptosis in ASC-like CAFs, also reduced pancreatic tumor growth and ECM deposition while promoting metastases. Single cell RNA sequencing demonstrated that depletion of either Pdgfrb+ or ASC-like CAFs decreased frequencies of tumor endothelial cells and viable cancer cells. However, while depletion of Pdgfrb+ CAFs led to stronger induction of cancer cell aggressiveness markers, depletion of ASC-like CAFs had an opposite effect on remaining CAFs. Depletion of ASC-like CAFs using D-CAN also led to higher infiltration of cytotoxic T-lymphocytes and B-lymphocytes. Administration of anti-PD-L1 antibody (aPDL1), which inhibits the immune checkpoint, had a stronger suppressive effect on tumor growth when combined with D-CAN in both female and male mice. Liver metastases were also reduced by the D-CAN / aPDL1 combination more effectively than by aPDL1 alone in female mice. We conclude that improved approaches to target ASC-like CAFs may be effective in combination with immunotherapy.