Abstract
Simple SummaryPancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate of all major cancers and, disappointingly, neither immune- nor stroma-directed therapies are found to improve upon the current standard of care. Among the most challenging aspects of PDAC biology which impede clinical success are the physiological features of the pancreatic cancer microenvironment (TME), including the presence of a highly fibrotic extracellular matrix marked by perineural invasion and an immunosuppressive milieu. Many current strategies for PDAC therapy are focused on altering these features to improve therapeutic efficacy. This review discusses the recent investigations using organotypic tumor slices as a model system to study cellular and extracellular interactions of the pancreatic TME. Future studies utilizing such models may provide new insights into the TME by identifying mechanisms of communication between multiple cell types and investigating novel therapeutic approaches for personalized cancer therapy. Organotypic tissue slices prepared from patient tumors are a semi-intact ex vivo preparation that recapitulates many aspects of the tumor microenvironment (TME). While connections to the vasculature and nervous system are severed, the integral functional elements of the tumor remain intact for many days during the slice culture. During this window of time, the slice platforms offer a suite of molecular, biomechanical and functional tools to investigate PDAC biology. In this review, we first briefly discuss the development of pancreatic tissue slices as a model system. Next, we touch upon using slices as an orthogonal approach to study the TME as compared to other established 3D models, such as organoids. Distinct from most other models, the pancreatic slices contain autologous immune and other stromal cells. Taking advantage of the existing immune cells within the slices, we will discuss the breakthrough studies which investigate the immune compartment in the pancreas slices. These studies will provide an important framework for future investigations seeking to exploit or reprogram the TME for cancer therapy.
Highlights
They observed that stroma regions adjacent to the epithelial cancer cells contained fewer CD8 T cells, but more regulatory T cells (T regs) and tumorassociated macrophages (TAMs). This unique arrangement of immune cells was found in lymphatic tissues [32]. These findings suggested that the cancer cells interacted with the surrounding stroma to block the infiltration of cytotoxic T cells and attract immunosuppressive cells, such as T regs and TAMs
While drug modeling in slice cultures may accurately predict an in vivo response, the 3D organoids derived from patients are a renewable and scalable resource
It should be noted that the drug testing in slice cultures might be more appropriate when an investigational drug is dependent on multiple aspects of the pancreatic tumor microenvironment since 3D organoids only contain epithelial cells
Summary
Incapable of self-sustenance, cancer cells shape their local microenvironment to provide the basic necessities for their survival: (1) growth factors to support cell proliferation, (2) a vasculature for the delivery of oxygen and nutrients, (3) stromal matrix deposition for a stable cytoarchitecture, and (4) shelter from immune surveillance These requirements to maintain cancer cell survival are supplied by multiple cell types including endothelial, fibroblast, nerve, and immune cells. The additional models which recapitulate human pathophysiology and disease progression are needed To this end, ex vivo models including tumor organoids and organotypic slices were developed from human specimens during the last ten years [5,6,7,8].
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