Depletion of Adipose Stroma-Like Cancer-Associated Fibroblasts Potentiates Pancreatic Cancer Immunotherapy

Immune checkpoint blockade therapy, transformative in some cancer types, has remained ineffective for patients with pancreatic cancer. The effects of subpopulations of cancer-associated fibroblasts (CAF) on cancer progression and therapy resistance are incompletely understood. In this study, the roles of CAFs expressing platelet-derived growth factor receptor β (Pdgfrb) and of CAFs expressing markers of adipose stromal cells (ASC) were analyzed in mice with pancreatic ductal adenocarcinoma. Ablation of Pdgfrb+ cells resulted in suppression of primary pancreatic tumor growth, reduction of extracellular matrix 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 extracellular matrix 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, whereas 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-PDL1 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.

This study shows that populations of CAFs have distinct effects on pancreatic cancer progression and shows that depletion of CAFs expressing adipose markers potentiates tumor/metastasis suppression effects of immune checkpoint blockade.