Macrophage and Neutrophil Interactions in the Pancreatic Tumor Microenvironment Drive the Pathogenesis of Pancreatic Cancer

Abstract

Despite modest improvements in survival in recent years, pancreatic adenocarcinoma remains a deadly disease with a 5-year survival rate of only 9%. These poor outcomes are driven by failure of early detection, treatment resistance, and propensity for early metastatic spread. Uncovering innovative therapeutic modalities to target the resistance mechanisms that make pancreatic cancer largely incurable are urgently needed. In this review, we discuss the immune composition of pancreatic tumors, including the counterintuitive fact that there is a significant inflammatory immune infiltrate in pancreatic cancer yet anti-tumor mechanisms are subverted and immune behaviors are suppressed. Here, we emphasize how immune cell interactions generate tumor progression and treatment resistance. We narrow in on tumor macrophage (TAM) spatial arrangement, polarity/function, recruitment, and origin to introduce a concept where interactions with tumor neutrophils (TAN) perpetuate the microenvironment. The sequelae of macrophage and neutrophil activities contributes to tumor remodeling, fibrosis, hypoxia, and progression. We also discuss immune mechanisms driving resistance to standard of care modalities. Finally, we describe a cadre of treatment targets, including those intended to overcome TAM and TAN recruitment and function, to circumvent barriers presented by immune infiltration in pancreatic adenocarcinoma.

Zebrafish Xenograft Model for Studying Pancreatic Cancer-Instructed Innate Immune Microenvironment

“…At the early stage of zebrafish larvae development, macrophages and neutrophils are two major populations in the innate immune system. Both macrophages and neutrophils have been shown to regulate anti-tumor immunity and immune evasion [ 9 ]. In our research, PANC1 and BxPC3 recruited more coro1a: GFP + innate immune cells to the TME compared to AsPC1 cells, and the co-localization of coro1a: GFP + cells with the tumor cells was increased from 1 dpi to 4 dpi by three-fold for PANC1 and BxPC3.…”

“…However, tumor cells also develop mechanisms to evade immune surveillance and could mold myeloid cells to serve the tumor. Functionally, tumor-associated myeloid cells are often divided into anti- or pro-tumor subgroups [ 9 , 10 , 11 ]. The anti-tumoral group are associated with immunostimulatory cells with the secretion of pro-inflammatory cytokines (e.g TNF-α, IL-12, and IL-6).…”

“…These studies support the idea that the macrophage is a promising target for PDAC therapy. Neutrophils are another prominent innate immune cell type in the PDAC TME [ 9 , 11 ]. Although the exact roles of neutrophils in PDAC are not well characterized, neutrophils have also been suggested to show different activation status from an immunostimulatory (N1-like) type to immunosuppressive (N2-like) type, similar to macrophages [ 9 ].…”

“…Neutrophils are another prominent innate immune cell type in the PDAC TME [ 9 , 11 ]. Although the exact roles of neutrophils in PDAC are not well characterized, neutrophils have also been suggested to show different activation status from an immunostimulatory (N1-like) type to immunosuppressive (N2-like) type, similar to macrophages [ 9 ]. It is known that macrophages could interact with neutrophils together to induce an innate and adaptive immunosuppressive TME.…”

Increased neutrophil infiltration as a body-wide effect in pancreatic cancer development

“…Neutrophils are thought to be recruited to the pancreatic tumors by chemokines and other signaling molecules released from tumor cells. 8 But how do neutrophils accumulate in non-tumor organs? Studies have shown that tumor-derived factors released from primary tumor site could systemically condition distant sites for potential metastases.…”