The tumour microenvironment in pancreatic cancer - clinical challenges and opportunities

Abstract

Metastatic pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumours despite the use of multi-agent conventional chemotherapy regimens. Such poor outcomes have fuelled ongoing efforts to exploit the tumour microenvironment (TME) for therapy, but strategies aimed at deconstructing the surrounding desmoplastic stroma and targeting the immunosuppressive pathways have largely failed. In fact, evidence has now shown that the stroma is multi-faceted, which illustrates the complexity of exploring features of the TME as isolated targets. In this Review, we describe ways in which the PDAC microenvironment has been targeted and note the current understanding of the clinical outcomes that have unexpectedly contradicted preclinical observations. We also consider the more sophisticated therapeutic strategies under active investigation - multi-modal treatment approaches and exploitation of biologically integrated targets - which aim to remodel the TME against PDAC.

Fig. 1 |. Targeting PDAC-associated stroma.

The role of the stroma to either promote or resist tumour formation and progression is influenced by the surrounding signals. Both cell–cell and paracrine interactions between cancer-associated fibroblasts (CAFs) and cancer cells are involved in programming the stroma. CAFs, key constituents of the pancreatic ductal adenocarcinoma (PDAC) stroma, are heterogeneous, and include myofibroblastic, inflammatory and antigen-presenting subtypes. Fibroblasts in proximity to cancer cells are induced by transforming growth factor-β (TGFβ) from cancer cells into myofibroblastic CAFs, producing the mechanical barrier that can be both tumour promoting and antitumour. Inflammatory CAFs, located in the stroma away from the cancer cells, are reprogrammed by cancer-secreted IL-1 to produce cytokines and chemokines (for example, IL-6), which further promote cancer growth. The subsequently developed antigen-presenting CAFs, which express MHC class II molecules, modulate the immune cells in the stroma. Approaches to deconstruct the stroma have included the use of matrix metalloproteinase (MMP) inhibitors, hyaluronidase, Sonic hedgehog (SHH) inhibitors, fibroblast activation protein (FAP) targeting agents and CXCR4 inhibitors. Ab, antibody; CAR, chimeric antigen receptor; ECM, extracellular matrix.

Fig. 2 |. Myeloid and T_reg targeting strategies to treat PDAC.

Antigen-presenting machinery relying on dendritic cells or inflammatory macrophages (TAM M1) and supported by helper T cells (CD4⁺ T cells) steers the antitumour immune response to eliminate pancreatic ductal adenocarcinoma (PDAC) — for example, via cytotoxic T cells (CD8⁺ T cells). However, myeloid-derived suppressor cells (MDSCs), anti-inflammatory tumour-associated macrophages (TAM M2), and regulatory T (T_reg) cells regulate these processes via several inhibitory pathways, establishing an immunosuppressive tumour microenvironment. Many strategies to abrogate or overcome these immunological targets have been proposed. Clinically tested approaches are listed in the corresponding boxes with the specific types and names of the agents in parentheses. APC, antigen-presenting cell; CSF-1R, colony-stimulating factor-1 receptor; CTLA-4, cytotoxic T lymphocyte antigen 4; GVAX, granulocyte–macrophage colony-stimulating factor secreting allogeneic pancreatic tumour cell vaccine; TCR, T cell receptor.

Fig. 3 |. Remodelling the PDAC microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is classically surrounded by desmoplastic stroma composed of cancer-associated fibroblasts and extracellular matrix (ECM). The stroma provides a dense mechanical barrier (both antitumour and tumour promoting) against vascularization, immune cell trafficking and cancer invasiveness. The tumour microenvironment is also characterized by the presence of multiple immunosuppressive pathways. Exploiting biologically integrated targets of the stroma (such as glutamine metabolism, transforming growth factor-β (TGFβ) and focal adhesion kinase (FAK) signalling) and the immunosuppressive pathways is the most likely approach to remodel the tumour microenvironment into an effective antitumour environment. MDSC, myeloid-derived suppressor cell; T_reg cell, regulatory T cell.