CSF1R+ Macrophages Sustain Pancreatic Tumor Growth through T Cell Suppression and Maintenance of Key Gene Programs that Define the Squamous Subtype

Abstract

SummaryPancreatic ductal adenocarcinoma (PDAC) is resistant to most therapies including single-agent immunotherapy and has a dense desmoplastic stroma, and most patients present with advanced metastatic disease. We reveal that macrophages are the dominant leukocyte population both in human PDAC stroma and autochthonous models, with an important functional contribution to the squamous subtype of human PDAC. We targeted macrophages in a genetic PDAC model using AZD7507, a potent selective inhibitor of CSF1R. AZD7507 caused shrinkage of established tumors and increased mouse survival in this difficult-to-treat model. Malignant cell proliferation diminished, with increased cell death and an enhanced T cell immune response. Loss of macrophages rewired other features of the TME, with global changes in gene expression akin to switching PDAC subtypes. These changes were markedly different to those elicited when neutrophils were targeted via CXCR2. These results suggest targeting the myeloid cell axis may be particularly efficacious in PDAC, especially with CSF1R inhibitors.

MAP Kinase inhibition reshapes tumor microenvironment of mouse pancreatic cancer by depleting anti-inflammatory macrophages

“…Using available PDA transcriptome data from the ICGC and the TCGA consortia, we found that levels of gene expression signatures indicative of MAP kinase activity (Biocarta_ERK_Pathway and MAPK Signature (21)) were higher in PDA subtypes (squamous/basal-like/quasimesenchymal) characterized by abundance of macrophage-related transcripts and immunosuppressive signaling (7,13,14) ( Figure 1A and Supplementary Figure 1A-B ). The enrichment of MAPK activity signatures in aggressive molecular subtype of PDA was also confirmed in additional 14 datasets of PDA ( Supplementary Figure 1C-D ).…”

“…Pharmacological and genetic depletion of myeloid cells (i.e., macrophages or neutrophils) in autochthonous model of PDA has been shown to dramatically alter gene programs that specify molecular subtypes (13,14). Investigation of immune-related cell signatures in bulk RNA sequencing has proven useful to estimate the composition of immune cell populations as well as transcriptional programs underpinning mechanisms of immune regulation (7,22).…”

“…Moreover, we show that depletion of macrophages is seen early during the course of the in vivo treatment, likely due to increased drug sensitivity of M2 macrophages compared to M0 and M1. Tumor-associated macrophages are prominent mediators of T cell exclusion (14) (45). Accordingly, we found that MEKi-induced TAM depletion was associated to increased infiltration of CD8+ T cells.…”

“…A hallmark of the PDA squamous subtype is gene programs associated with squamous differentiation and macrophage function (7). A previous study has shown that depletion of macrophages in KPC using a CSF1R inhibitor resulted in “subtype switch” and reduced immunosuppressive microenvironment (14). In our model, we also observed a “switch away” from the squamous/basal-like/quasimesenchymal subtype following MEKi treatment.…”

“…Depletion of myeloid cells/macrophages through genetic and pharmacological approaches have demonstrated promising for increasing efficacy of immune checkpoint inhibitors (13,14). Of these myeloid cell populations, tumor-associated macrophages play a relevant role in tumor progression (14), resistance to chemotherapy (15,16), and immune tolerance in PDA (17).…”