Understanding and Targeting Natural Killer Cell-Cancer-Associated Fibroblast Interactions in Pancreatic Ductal Adenocarcinoma

SIMPLE SUMMARY: Pancreatic cancer is an aggressive disease with a 5-year survival rate of less than 10%. Current therapies can be ineffective due to immune suppression and fibrosis (tissue scarring) that prevents cancer cells from being killed. This review article discusses the relevance of examining how natural killer (NK) cells, immune cells involved in the anti-cancer immune response, interact with cancer-associated fibroblasts (CAFs), which cause fibrosis, in pancreatic cancer. Understanding how these cell types interact may provide insights to guide the development of novel targeted therapies to increase immune response and survival in patients with pancreatic cancer. ABSTRACT: Interactions between natural killer (NK) cells and cancer-associated fibroblasts (CAFs) comprise a relevant but relatively understudied crosstalk relationship within the tumor microenvironment (TME). This review discusses the relevance of both natural killer cell and cancer-associated fibroblast function and activity in cancers, with an emphasis on pancreatic ductal adenocarcinoma (PDAC), incorporating additional insights from other malignancies to inform future directions for research. We describe what is currently known about NK cell-CAF crosstalk and their molecular interactions, how it is possible to exploit NK cell cytotoxicity in tumors and how to target CAFs to enhance efficacy of cancer therapies and cytotoxic immune cells. Although not previously tested in combination, there is an abundance of evidence demonstrating that targeting tumor-promoting CAFs and exploiting NK cells, separately, are beneficial as therapeutic strategies. This raises the possibility that a novel combination regimen addressing these two cell targets may be even more beneficial to eradicate PDAC and other solid tumors.