Abstract
Simple SummaryPancreatic 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.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.
Highlights
The tumor microenvironment (TME) is a mixture of cancer cells, fibroblasts, extracellular matrix (ECM) proteins, endothelial cells, and immune cells, including myeloid derived suppressor cells (MDSCs), macrophages, neutrophils, and antigen-presenting dendritic cells (DCs); T-cells and natural killer cells
Complex activating and inhibitory signaling responses in natural killer (NK) cells mediate their function. Understanding this complex biology has allowed NK cell cytotoxicity to be exploited in cancer therapies, like utilizing cytokine therapies, chimeric antigen receptor (CAR)-NK cell therapy, immune checkpoint inhibitors (ICIs) for CTLA-4, PD-1 (CD279) and PD-L1 (CD274), and the use of inhibitors of inhibitory NK cell receptorligand interactions
Despite lower major histocompatibility complex (MHC) I presentation, cancer cells are resistant to NK cell mediated lysis, which can be caused by multiple mechanisms, including: (1) increasing expression of NK cell inhibitory ligands, (2) secreting tumor growth factor β (TGFβ) to prevent NK cell activation, (3) secreting soluble NK cell ligands into the ECM to prevent NK cell contact with the tumor cell, a process that may be mediated by metalloproteinases (MMPs) from both cancer cells and cancer-associated fibroblasts (CAFs) [36,37,38,39]; or (4) interact with other cellular components of the TME, like CAFs [12,36]
Summary
The TME is a mixture of cancer cells, fibroblasts, extracellular matrix (ECM) proteins, endothelial cells, and immune cells, including myeloid derived suppressor cells (MDSCs), macrophages, neutrophils, and antigen-presenting dendritic cells (DCs); T-cells and natural killer cells All of these cellular components interact to mediate or inhibit tumor progression, but relationships between NK cells and CAFs have not been well studied. CAFs impose therapeutic challenges by exhibiting plasticity [3,4,5,6,7,8,9], illustrating the need to further understand the function of CAF subpopulations in order to develop improved targeted therapies against tumor-promoting CAFs. A combination of depleting CAFs and enhancing NK cell activity may increase immune cell infiltration into tumors by overcoming immune suppressive tumor-promoting. The aim of this review is to contextualize available knowledge about these NK cell-CAF interactions, in the hope of stimulating further research in this area
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