Targeting Aggressive Fibroblasts to Enhance the Treatment of Pancreatic Cancer

ABSTRACT

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant cancer entities, which is characterized by abundant desmoplastic stroma. The stroma consists of extracellular matrix, infiltrating immune cells, cancer-associated fibroblasts (CAFs) and others. Depending on environmental cues, CAFs can be highly heterogeneous and play context-dependent roles in PDAC progression.

Areas covered

In this article, we discuss the biological significance of CAFs heterogeneity (oncogenic vs. tumor-suppressive) in pancreatic carcinogenesis. In particular, the complex interaction between CAFs and infiltrating immune cells has a determinant role in defining the stromal composition. A subset of PDAC patients may benefit from anti-CAFs therapy.

Expert opinion

Co-defined by CAFs and infiltrating immune cells, the prognostic stroma signature is clinically relevant in a subset of human PDAC. This is the patient population which may benefit from future anti-stroma or anti-CAFs therapies. To consider CAF heterogeneity is crucial for designing anti-stroma studies. Here, reliable and traceable subtype-specific markers for CAFs are urgently needed to dissect the biological impact of CAF heterogeneity on PDAC development spatiotemporally. Given the significant contribution of CAFs to immunosuppressive microenvironment of PDAC, it is conceivable to combine anti-CAFs therapy with immunotherapy. To implement a CAF-subtype specific therapy is crucially important to improve the effectiveness of current treatments including chemotherapies and immunotherapy.

KEYWORDS:

• Pancreatic cancer
• desmoplastic reaction
• CAF
• CAF heterogeneity
• PSC

Article highlights

• Stroma activity is regarded as an independent prognostic factor in PDAC.

• PDAC cancer cells and CAFs are regulated reciprocally.

• Heterogeneous CAFs can both promote and restrain PDAC progression.

• CAFs induce a highly immunosuppressive microenvironment in PDAC. Anti-CAFs agents can become promising adjuvant therapies to promote the efficiency of immunotherapy in PDAC.

This box summarizes key points contained in the article.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper is not funded.