Abstract
The stroma-rich, immunosuppressive microenvironment is a hallmark of pancreatic ductal adenocarcinoma (PDA). Tumor cells and other cellular components of the tumor microenvironment, such as cancer associated fibroblasts, CD4+ T cells and myeloid cells, are linked by a web of interactions. Their crosstalk not only results in immune evasion of PDA, but also contributes to pancreatic cancer cell plasticity, invasiveness, metastasis, chemo-resistance, immunotherapy-resistance and radiotherapy-resistance. In this review, we characterize several prevalent populations of stromal cells in the PDA microenvironment and describe how the crosstalk among them drives and maintains immune suppression. We also summarize therapeutic approaches to target the stroma. With a better understanding of the complex cellular and molecular networks in PDA, strategies aimed at sensitizing PDA to chemotherapy or immunotherapy through re-programing the tumor microenvironment can be designed, and in turn lead to improved clinical treatment for pancreatic cancer patients.
Highlights
Pancreatic ductal adenocarcinoma (PDA) is the most common form of pancreatic cancer, the third leading cause of cancer related death in the United States, with a 5-year survival rate of around 10% [1, 2]
This review summarizes the crosstalk between several key cell types that are dominant within the immunosuppressive tumor microenvironment (TME) of pancreatic cancer and discusses the most promising immune regulatory approaches to activate anti-tumor immune responses in PDA
Using a combination of mass cytometry, single-cell RNA sequencing and multiplex immunohistochemistry, we found increased markers of CD8+ T cell dysfunction with an up-regulation of T cell immunoglobulin and ITIM domains (TIGIT) in PDA compared to non-malignant pancreas samples; further, the dysfunctional status of CD8+ T cells was more pronounced at later stages of carcinogenesis [11]
Summary
Pancreatic ductal adenocarcinoma (PDA) is the most common form of pancreatic cancer, the third leading cause of cancer related death in the United States, with a 5-year survival rate of around 10% [1, 2]. This review summarizes the crosstalk between several key cell types that are dominant within the immunosuppressive TME of pancreatic cancer and discusses the most promising immune regulatory approaches to activate anti-tumor immune responses in PDA.
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