Exploring the role of antigen-presenting cancer-associated fibroblasts and CD74 on the pancreatic ductal adenocarcinoma tumor microenvironment.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has proven to be a formidable cancer primarily due to its tumor microenvironment (TME). This highly desmoplastic, hypoxic, and pro-inflammatory environment has not only been shown to facilitate the growth and metastasis of PDAC but has also displayed powerful immunosuppressive capabilities. A critical cell involved in the development of the PDAC TME is the fibroblast, specifically the antigen-presenting cancer-associated fibroblast (apCAF). The pro-inflammatory environment of PDAC induces the proliferation of apCAFs, promoting immunosuppression through immune cell inactivation, immune response regulation, and expression of CD74. In conjunction with apCAFs and tumor cells, CD74 serves as a versatile promoter of PDAC by preventing tumor antigen-expression on tumor cells, upregulating the expression of immunosuppressive chemical mediators, and activating proliferative pathways to induce PDAC malignancy. This review will highlight critical mediators and pathways that promote the PDAC stroma and TME with its hypoxic and immunosuppressive properties. Further, we will highlight the nature of apCAFs and CD74, their specific roles in the PDAC TME, and their potential as targets for immunotherapy.