Inflammatory networks and immune surveillance of pancreatic carcinoma

Abstract

Cancer-associated inflammation plays an important role in restraining anti-tumor immunity, particularly in pancreatic ductal adenocarcinoma (PDA) for which a massive infiltration of immunosuppressive leukocytes into the tumor stroma is an early and consistent event in oncogenesis. Intratumoral effector T cells are rare. This pathophysiology is in contrast to many other solid tumors for which infiltration of effector T cells is often prominent, associated with improved clinical outcomes, and mechanistically contributes to tumor immunoediting that ultimately can mediate immune escape. In PDA, increasing evidence suggests that the ras oncogene drives an inflammatory program that establishes immune privilege in the tumor microenvironment. Indeed, PDA cells might remain intrinsically sensitive to T cell killing because they have never been exposed to T cell selective pressure in vivo. In support of this hypothesis, recent studies demonstrate that derailing immune suppressive pathways in the PDA microenvironment, such as tumor derived GM-CSF, facilitates T-cell mediated tumor rejection. These findings carry major implications for the development of novel, combination immunotherapies for pancreatic cancer.

Figure 1

The PDA microenvironment is characterized by a dense desmoplastic reaction and prominent infiltration of leukocytes. (A) H&E stain and (B) immunohistochemistry for CD45 of a representative primary PDA lesion from a tumor-bearing KPC mouse. Scale bars, 100 μM.

Figure 2

In pancreatic ductal adenocarcinoma, the ras oncogene induces an inflammatory program that establishes immune suppression and ultimately immune privilege in the tumor microenvironment. One critical mediator is tumor-derived GM-CSF which drives the accumulation of immature myeloid cells that then directly suppress infiltrating T cells.