Pancreas resident macrophage-induced fibrosis has divergent roles in pancreas inflammatory injury and PDAC

Abstract

Tissue-resident macrophages (TRMs) are long-lived cells that maintain locally and can be phenotypically distinct from monocyte-derived macrophages (MDMs). However, whether TRMs and MDMs have functional distinction under differing pathologies is not understood. Here, we show a significant portion of macrophages that accumulated during pancreatitis and pancreatic cancer were expanded from TRMs. We further established that pancreas TRMs have a distinct extracellular matrix remodeling phenotype that was critical for maintaining tissue homeostasis during inflammation. Loss of TRMs led to exacerbation of severe pancreatitis and animal death, due to impaired acinar cell survival and recovery. In pancreatitis, TRMs elicited protective effects by triggering the accumulation and activation of fibroblasts, which was necessary for initiating fibrosis as a wound healing response. The same TRM-driven fibrosis, however, drove pancreas cancer pathogenesis and progression. Together, these findings indicate that TRMs play divergent roles in the pathogenesis of pancreatitis and cancer through regulation of stromagenesis.

On the Biology and Therapeutic Modulation of Macrophages and Dendritic Cells in Cancer

“…At later stages of tumor progression, AMs were found to be reorganized to the periphery of established tumor lesions, indicating that the contribution of AMs to antitumor immunity differs at different stages of disease (Loyher et al 2018). Similarly, in pancreatic cancer, profibrotic RTMs of the pancreas make up a significant portion of tumorinfiltrating macs (Zhu et al 2017, Baer et al 2022, and the specific depletion of RTMs reduced tumor burden significantly, whereas perturbing the accumulation of monocyte-derived macs failed to affect tumor load, suggesting that pancreatic RTMs play a central role in pancreatic cancer progression (Baer et al 2022). In the brain, microglia play a prominent role in the neoplasia of the central nervous system; in glioblastoma multiforme, blocking the M-CSF (macrophage colonystimulating factor) receptor (CSF-1R) greatly increased survival and induced cancer regression by modulating the microglial molecular program and subsequent phenotype (Pyonteck et al 2013).…”

Tumor-specific CD4 T cells instruct monocyte fate in pancreatic ductal adenocarcinoma

“…Resident macrophages appear predisposed to adopt a protumor state and contribute to tumor growth. 24 , 65 – 67 Our observations suggest that tissue-resident macrophages are resistant toward rewiring to an immunostimulatory state and that, in the absence of tumor-specific CD4 T cells, monocytes adopt tissue-resident features. Thus, a fate-mapping approach is likely critical for distinguishing monocyte-derived from embryonic-derived TAMs.…”

“…While Arg1 + 39 , 71 and Lyve1 + 67 macrophages are immunosuppressive and promote tumor progression in other cancer models, we did not directly test if deletion of these subsets led to improved outcomes in PDA. While CD40L is reported to be mostly restricted to CD4 T cells 72 , 73 and CD4 T cells are potent producers of IFNγ, 74 , 75 we did not test the CD4 T cell intrinsic role of these molecules on macrophage phenotype.…”

Tumor-specific CD4 T cells instruct monocyte differentiation in pancreatic ductal adenocarcinoma

“…Therefore, the identification of factors that can interfere with the differentiation of monocytes into the MHCII lo macrophage or promote the differentiation of monocytes into the MHCII hi subset represent key therapeutic targets. In addition, tissue-resident macrophages appear predisposed to adopt a protumor phenotype and contribute to tumor growth in PDA 23,69 , as well as other cancer models 70,71 . These observations suggest that tissue-resident macrophages may be particularly resistant toward rewiring to an immunostimulatory state which warrants further investigation.…”