Pancreatic cancer stroma: an update on therapeutic targeting strategies

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality in the Western world with limited therapeutic options and dismal long-term survival. The neoplastic epithelium exists within a dense stroma, which is recognized as a critical mediator of disease progression through direct effects on cancer cells and indirect effects on the tumour immune microenvironment. The three dominant entities in the PDAC stroma are extracellular matrix (ECM), vasculature and cancer-associated fibroblasts (CAFs). The ECM can function as a barrier to effective drug delivery to PDAC cancer cells, and a multitude of strategies to target the ECM have been attempted in the past decade. The tumour vasculature is a complex system and, although multiple anti-angiogenesis agents have already failed late-stage clinical trials in PDAC, other vasculature-targeting approaches aimed at vessel normalization and tumour immunosensitization have shown promise in preclinical models. Lastly, PDAC CAFs participate in active cross-talk with cancer cells within the tumour microenvironment. The existence of intratumoural CAF heterogeneity represents a paradigm shift in PDAC CAF biology, with myofibroblastic and inflammatory CAF subtypes that likely make distinct contributions to PDAC progression. In this Review, we discuss our current understanding of the three principal constituents of PDAC stroma, their effect on the prevalent immune landscape and promising therapeutic targets within this compartment.

Fig. 1 |. The desmoplastic response is a key feature in human and mouse pDaC.

Haematoxylin and eosin stained sections of pancreatic ductal adenocarcinoma (PDAC) tissues from the KPC genetically engineered mouse model (part a) and human (part b). Both mouse and human PDAC tissues display an abundance of fibrosis (black arrows) admixed with the malignant epithelium (white arrows). This dense, fibrotic stroma is known as the desmoplastic response and is primarily composed of an abundance of fibroblasts and collagen. Magnification ×20. The schematic of the principal components comprising the desmoplastic response in PDAC (part c) shows an increase in fibroblasts, hyaluronic acid and the deposition of extracellular matrix proteins (mainly collagens and fibronectin), which are a hallmark of PDAC desmoplasia. Part a courtesy of A. Maitra. Part b courtesy of R. Brekken.

Fig. 2 |. Therapeutic targets in the extracellular matrix of pDaC.

a | Hyaluronic acid degradation by pegylated recombinant human hyaluronidase 20 (PEGPH20) decreases intratumoural pressure, leading to improved chemotherapy delivery in pancreatic ductal adenocarcinoma (PDAC) genetically engineered mouse models. b | Activated Rho-associated protein kinase (ROCK) in the PDAC tumour cell can lead to extracellular matrix remodelling through upregulation of matrix metalloproteinases (MMPs). This process favours metastasis and decreased microvessel density (MVD), which then leads to poor tumour perfusion and decreased tumour drug delivery. Fasudil is a small-molecule inhibitor of ROCK with anti-PDAC activity in preclinical models. c | When activated, focal adhesion kinase (FAK) can decrease CD8⁺ T cell infiltration into the PDAC tumour microenvironment and increase the desmoplastic response, which can hinder drug delivery to the tumour. Defactinib is a small-molecule inhibitor of FAK under clinical evaluation for the treatment of PDAC in combination with an immune checkpoint inhibitor. CAF, cancer-associated fibroblast.

Fig. 3 |. Vascular normalization as a therapeutic strategy in pDaC.

The pancreatic ductal adenocarcinoma (PDAC) tumour microenvironment features an inefficient, leaky vasculature with poor pericyte coverage, which is associated with poor tumour perfusion leading to hypoxia and suboptimal drug delivery. Tumour vasculature normalization by blocking the vascular endothelial growth factor (VEGF)–VEGFR2 axis can improve pericyte coverage and tumour perfusion, leading to decreased hypoxia, increased drug delivery and CD8⁺ T cell trafficking into the tumour through the action of the leukocyte adhesion molecules ICAM and VCAM.

Fig. 4 |. Immunohistochemical analysis of pancreatic ductal adenocarcinoma CaF subtypes.

The pancreatic cancer tumour microenvironment features distinct populations of myofibroblastic cancer-associated fibroblasts (CAFs) termed myCAFs and inflammatory CAFs termed iCAFs, which have been shown to be located juxtatumoural and distal to the cancer epithelium, respectively. The image is that of a moribund genetically engineered mouse model of PDAC. Platelet-derived growth factor receptor-α (brown) is a marker of iCAFs whereas α-smooth muscle actin (blue) is a marker of myCAFs. The ductal marker, SOX9 (red), stains for cancer epithelium. Image courtesy of R. Brekken (magnification ×20).

Fig. 5 |. Intratumoural fibroblast heterogeneity in pDaC.

Protumour inflammatory cancer-associated fibroblasts (iCAFs) and antitumour myofibroblastic cancer-associated fibroblasts (myCAFs) are produced when resident pancreatic fibroblasts receive paracrine and cell-contact cues from pancreatic ductal adenocarcinoma (PDAC) cells, respectively , within the tumour microenvironment. Tumour cell-derived IL-1α aids in the generation of iCAFs, which secrete LIF and propagate the iCAF phenotype. IL-1β also acts to maintain the iCAF phenotype through autocrine signalling. iCAFs upregulate a host of inflammatory cytokines, such as IL-6 and granulocyte colony-stimulating factor (G-CSF), in addition to contributing to local collagen deposition. Putative markers for iCAFs are platelet derived growth factor receptor-α (PDGFRα) and CXCL12. When IL-1 receptor (IL-1R) is activated by IL-1 ligands, IL-1 receptor-associated kinase 4 (IRAK4) is also activated, which in turn leads to the activation of IKKβ. These events lead to the liberation of nuclear factor-κB (NF-κB) from inhibitory proteins, enabling it to translocate to the nucleus where it acts as a transcription factor for a host of inflammatory genes that drive the iCAF phenotype^,. iCAFs have also been shown to signal through the JAK–STAT signalling pathway. Cell contact between PDAC cells and juxtatumoural fibroblasts generates myCAFs through transforming growth factor-β (TGFβ) signalling. Putative markers for myCAFs are fibroblast-specific protein 1 (FSP1) and/or α-smooth muscle actin (αSMA). Mesenchymal stem cell-derived cancer-associated fibroblasts (mscCAFs) are recruited from the bone marrow and produce granulocyte–macrophage colony-stimulating factor (GM-CSF) locally in the tumour microenvironment, contributing to polarization of macrophages towards an immunosuppressive phenotype and blunting of a robust T cell response against the tumour. mscCAFs are positive for CD44, CD49, CD73 and CD90. Lastly , major histocompatibility complex (MHC) class II-expressing CAFs (apCAFs) have demonstrated the ability to present antigen to CD4⁺ T cells. Shh, sonic hedgehog.

Fig. 6 |. Therapeutic targets in pDaC CaFs.

a | Signalling of insulin-like growth factor 1 (IGF1) receptor (IGF1R) and AXL can lead to invasive and metastatic behaviour of pancreatic ductal adenocarcinoma (PDAC) tumour cells. Clinical data on IGF1R blockade have been unsuccessful, although preclinical data suggest possible merit in dual GAS6–AXL and IGF1–IGF1R blockade. A small-molecule inhibitor of AXL (TP-0903) is now in clinical trials for advanced PDAC. b | PDAC cancer-associated fibroblasts (CAFs) have increased vitamin D receptor (VDR) expression and decreased expression of lipid storage genes. When treated with calcipotriol (a synthetic form of vitamin D), these CAFs increase lipid storage gene expression and hinder epithelial-to-mesenchymal transition (EMT), chemoresistance and the action of myeloid-derived suppressor cells (MDSCs). Multiple clinical trials are underway to assess the benefit of vitamin D treatment in PDAC^,,. c | Retinoic acid signalling. PDAC CAFs are induced to assume a lipid storage phenotype when treated with all-trans retinoic acid (ATRA), which inhibits β-catenin nuclear localization and invasion of cancer cells. ATRA is being tested in a clinical trial of locally advanced or metastatic PDAC.