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Transcriptomic characterization of CD206- and CD206+ macrophages in human pancreatic islets and exocrine tissue

ABSTRACT: Macrophages reside in all organs and participate in homeostatic- and immune regulative processes. Little is known about pancreatic macrophage gene expression. CD206 is an endocytic receptor with prior use in subclassifying macrophages. In the present study, global gene expression was characterized in human pancreatic macrophage subpopulations. Flow cytometry was used to sort CD206- and CD206+ macrophages separately from pancreatic islets and exocrine tissue to high purity. RNA-seq generated transcriptomic profiles were then analyzed. Comparing CD206- with CD206+ macrophages, CD206- showed enrichment in proliferation and nucleic acid processing, glycolysis, pro-inflammatory and SPP1-associated gene sets while CD206+ showed enrichment in complement-, IL-10 and IL-2RA immune regulation, as well as scavenging-related gene sets. Two sets involved in immune regulation were enriched in islet CD206-, while various sets including some proinflammatory sets were enriched in exocrine CD206- macrophages. Fewer differences were found between CD206+ macrophages, with enrichment in two IL2-RA related gene sets in islets and eight gene sets in exocrine samples. Comparing macrophages between individuals with normoglycemia, elevated HbA1c or type 2 diabetes, only a few diverse differentially expressed genes were identified. This work characterizes global gene expression and identifies differences between CD206- and CD206+ macrophage populations within the human pancreas.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281600 | GEO | 2025/04/16

REPOSITORIES: GEO

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Project description:The direct and indirect effects of targeting specific tumor-associated macrophage (TAM) subsets in cancer are not well-defined. TAM targeting strategies are frequently based on the ‘M1’ or ‘M2’ polarization categories, even as substantial data challenges this binary modeling of macrophage cell state. One molecule consistently referenced as a delineator of a putative immunosuppressive ‘M2’ state is the surface protein CD206. We thus made a novel conditional CD206 (Mrc1) knock-in mouse to specifically visualize and/or deplete CD206+ TAMs and assess their correspondence with pro-tumoral immunity. Early, but not late depletion of CD206+ macrophages and monocytes (here, ‘Mono/Macs’) led to an indirect loss of a key anti-tumor network of NK cells, conventional type I dendritic cells (cDC1) and CD8 T cells. Among myeloid cells, we found that the CD206+ TAMs are the primary producers of CXCL9, and able to differentially attract activated CD8 T cells. In contrast, a population of stress-responsive TAMs (“Hypoxic” or Spp1+) and immature monocytes, which lack CD206 expression and become prominent following early depletion, expressed markedly diminished levels of CXCL9. Those NK and CD8 T cells which enter CD206-depleted tumors express vastly reduced levels of the corresponding receptor Cxcr3, the cDC1-attracting chemokine Xcl1 and cDC1 growth factor Flt3l transcripts. Consistent with the loss of this critical network, early CD206+ TAM depletion decreased tumor control by antigen specific CD8 T cells in mice. Likewise, in humans, the CD206Replete, but not the CD206Depleted Mono/Mac gene signature correlated robustly with CD8 T cell, NK cell and stimulatory cDC1 gene signatures and transcriptomic signatures skewed towards CD206Replete Mono/Macs associated with better survival. Together, these findings negate the unqualified classification of CD206+ ‘M2-like’ macrophages as immunosuppressive and provide further evidence of the context-dependence of macrophage function in tumors.

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Transcriptomic characterization of CD206- and CD206+ macrophages in human pancreatic islets and exocrine tissue

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