Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy, in part because of a high rate of metastasis, that commonly occurs to the liver. Immunosuppressive macrophages accumulate at PDAC metastases, but the heterogeneity within this population and whether these macrophages could be therapeutically targeted is not fully understood. To study macrophage populations accumulating at PDAC liver metastases, Astuti and colleagues performed bulk RNA sequencing on liver biopsies from patients with treatment-naive, metastatic PDAC and found that these lesions had increased macrophage content and depletion of CD8+ T cells. Using a mouse model of PDAC liver metastasis, metastasis-associated macrophages were isolated and analyzed via single-cell RNA sequencing, which revealed a co-occurrence of immunosuppressive and immunostimulatory macrophage subsets and substantial heterogeneity compared with tumor-free livers. Specifically, macrophages within the tumor cores consisted of monocyte-derived macrophages, and one subset of these macrophages was enriched for genes involved in phagocytosis and apoptotic cell clearance, reminiscent of a subset of macrophages that clear dying cells in tissue repair and disease during efferocytosis. Moreover, hepatic necrosis is induced upon early metastatic spreading to the liver and was shown to promote Arg1 expression on efferocytic macrophages, which is a marker of immunosuppressive macrophages, and pharmacologic blockade of efferocytosis sufficiently blocked Arg1 upregulation, increased infiltration of CD8+ T cells, and reduced metastases to the liver. Additionally, the lysosomal gene progranulin (Grn) was upregulated in metastatic efferocytic macrophages, and depletion of Grn abrogated the upregulation of Arg1 and suppression of CD8+ T cells observed upon efferocytosis induction with macrophage-specific depletion of Grn also reducing metastatic tumor burden. Mechanistically, Grn enabled lysosomal cargo processing during efferocytosis by mediating lysosomal acidification through interactions with CFTR, and CFTR inhibition in PDAC liver metastasis murine models restrained metastasis, reduced Arg1 expression in macrophages, and increased CD8+ T-cell activation. In summary, macrophage-mediated efferocytosis is crucial for inducing PDAC liver metastasis and an immunosuppressive microenvironment, and blockade of this pathway represents a novel therapeutic strategy to inhibit PDAC metastasis.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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