CXCL10/CXCR3 signaling contributes to an inflammatory microenvironment and its blockade enhances progression of murine pancreatic precancerous lesions

Abstract

The development of pancreatic cancer requires recruitment and activation of different macrophage populations. However, little is known about how macrophages are attracted to the pancreas after injury or an oncogenic event, and how they crosstalk with lesion cells or other cells of the lesion microenvironment. Here, we delineate the importance of CXCL10/CXCR3 signaling during the early phase of murine pancreatic cancer. We show that CXCL10 is produced by pancreatic precancerous lesion cells in response to IFNγ signaling, and that inflammatory macrophages are recipients for this chemokine. CXCL10/CXCR3 signaling in macrophages mediates their chemoattraction to the pancreas, enhances their proliferation and maintains their inflammatory identity. Blocking of CXCL10/CXCR3 signaling in vivo shifts macrophage populations to a tumor promoting (Ym1+, Fizz+, Arg1+) phenotype, increases fibrosis and mediates progression of lesions, highlighting the importance of this pathway in PDA development. This is reversed when CXCL10 is overexpressed in PanIN cells.

Genomic analyses identify biological processes and functions between M1 and M2 macrophages

“…ITGAX is a proinflammatory gene that is expressed in muscle and correlates positively with glycemia 52 . Veethika Pandey et al found CXCL10 creates an inflammatory microenvironment and inhibits the progression of pancreatic precancerous lesions 53 . Yuan Zhuang et al demonstrated that inhibition of CCL5-CCR5 enhances M1 macrophage polarization 54 .…”

Ym1+ macrophages orchestrate fibrosis, lesion growth, and progression during development of murine pancreatic cancer

“…(2008) ; Bastea et al. (2019) ; Pandey et al. (2021) N/A Mouse: Primary bone marrow-derived macrophages Method: Zhang et al.…”

“…A population of alternatively activated macrophages (AAM), best characterized by expression of Chil3 (encodes Ym1), Arg1 , Fizz1 , IL1rn , and Il10 , can stimulate the growth of early pancreatic lesions (low-grade PanIN) via secretion of CCL2, IL-1ra, and other factors ( Bastea et al., 2019 ; Liou et al., 2017 ). Recent work suggests that these Ym1 + AAM at the earliest stages of tumor development do not originate from expansion of a tissue-resident population ( Pandey et al., 2021 ), but rather from infiltrating inflammatory macrophages after a polarization switch that is mediated by IL-13 secretion from PanIN ( Liou et al., 2017 ). Although a depletion of Ym1 + macrophages (i.e.…”

Generation of Hydrogen Peroxide and Downstream Protein Kinase D1 Signaling Is a Common Feature of Inducers of Pancreatic Acinar-to-Ductal Metaplasia

“…The mice were injected with 2 mL of 5% aged thioglycollate. Five days later, the mice were euthanized and the peritoneal macrophages were collected via a single injection of 10 mL RPMI-1640 plus 10% FBS into the peritoneal cavity and subsequent withdrawal (described in detail in [ 10 , 22 ]). The peritoneal exudate was centrifuged (233× g ) and washed with RPMI-1640 media plus 10% FBS before plating onto 10 cm tissue culture dishes.…”