Stromal reengineering to treat pancreas cancer

Abstract

Pancreatic ductal adenocarcinoma co-opts multiple cellular and extracellular mechanisms to create a complex cancer organ with an unusual proclivity for metastasis and resistance to therapy. Cell-autonomous events are essential for the initiation and maintenance of pancreatic ductal adenocarcinoma, but recent studies have implicated critical non-cell autonomous processes within the robust desmoplastic stroma that promote disease pathogenesis and resistance. Thus, non-malignant cells and associated factors are culprits in tumor growth, immunosuppression and invasion. However, even this increasing awareness of non-cell autonomous contributions to disease progression is tempered by the conflicting roles stromal elements can play. A greater understanding of stromal complexity and complicity has been aided in part by studies in highly faithful genetically engineered mouse models of pancreatic ductal adenocarcinoma. Insights gleaned from such studies are spurring the development of therapies designed to reengineer the pancreas cancer stroma and render it permissive to agents targeting cell-autonomous events or to reinstate immunosurveillance. Integrating conventional and immunological treatments in the context of stromal targeting may provide the key to a durable clinical impact on this formidable disease.

Fig. 1.

Complex network of stromal resistance in PDA. A number of distinct but often overlapping cellular and extracellular processes combine to create an immune-privileged and drug-free sanctuary that aids and abets tumor development and therapeutic resistance in pancreas cancer. These processes can be conceptualized as interacting modules that are largely driven by, and cooperate with, cell autonomous events (e.g. mutations in the Kras proto-oncogene) in tumor epithelial cells (TEC). This plethora of non-cell autonomous mechanisms also provides a novel landscape of therapeutic opportunities. (i) TEC: TEC produce cytokines [GM-CSF (granulocyte–macrophage colony-stimulating factor), G-CSF (granulocyte colony–stimulating factor), M-CSF (macrophage colony–stimulating factor)] that induce the expansion of immunosuppressive myeloid cells of both the granulocyte and monocyte lineage. TEC also produce chemokines (CCL2, CXCL1, CXCL2) that contribute to myeloid cell recruitment into the tumor parenchyma. TEC express PDL1 (our unpublished observations) and several immunosuppressive factors (TGFβ; IL-10; indoleamine 2,3-dioxygenase, IDO) that directly inhibit the functional activity of CD8 T cells. IDO is also implicated in the accumulation of Treg (data not shown). TEC produce TGFβ, fibroblast growth factor, platelet-derived growth factor, and Shh to influence PSC activation and proliferation. Lastly, TEC produce HA and collagen that profoundly alter fluid dynamics and pressures in the interstitium. (ii) Hematopoietic compartment: The immune contexture of PDA is biased toward immunosuppressive cell subsets that inhibit the recruitment, retention and activity of cytotoxic T lymphocytes. Typically, 50% or more of the cells in PDA are hematopoietic in origin. CD4⁺FoxP3⁺ Treg and TAM are significantly increased in preinvasive disease and are maintained at high frequency during invasive disease. Treg deploy an immunosuppressive arsenal including IL-10 and TGFβ. TAM are potently immunosuppressive in PDA via production of T-cell inhibitory factors [iNOS, arginase, and IL-10] and also express inhibitory ligands, such as PDL2. Immature myeloid cells with suppressive activity (MDSC) represent a heterogeneous population of immature granulocytic and monocytic progenitors that utilize a variety of immunosuppressive mechanisms including reactive oxygen species, arginase, iNOS, peroxynitrates, TGFβ and potentially IDO. (iii) Mesenchymal compartment: Activated PSC are a major source of inflammatory factors and ECM proteins. The secretion of CXCL12 may sequester CD8 T cells away from TEC and may also promote the migration of monocytes and/or Mo-MDSC. Activated PSC are also a principal source of fibrillar collagen. (iv) ECM: The inordinately high IFP in PDA is largely generated by a complex and dysregulated ECM. An inverted oncotic pressure gradient recruits fluid from the vasculature that binds HA in the interstitium. The swelling pressure generated by hydrated HA strains tethered collagen fibrils bound to surface receptors on TEC, PSC and immune cells. This applied tension triggers active contractile forces as the cells attempt to maintain tensional homeostasis. These combined passive and active forces contribute to the elevated IFP in PDA, presenting a primary biophysical barrier to cytotoxic drug delivery and perfusion. The impact of the specific ECM components on cell signaling in various cell types is incompletely understood, but targeting HA and other ECM components may alter critical biochemical signaling to infiltrating and resident cells to therapeutic advantage.