Liver macrophage subsets differentially regulate metastasis in pancreatic cancer

Abstract Metastasis is the main cause of morbidity and mortality in patients with cancer. In pancreatic ductal adenocarcinoma (PDA), the liver is the most common site of metastasis. During PDA progression, the liver microenvironment becomes altered to support metastatic seeding and colonization by disseminated tumor cells (DTC). Macrophages (MΦ), including liver-resident Clec4f+ Kupffer cells (KCs) and bone marrow derived MΦ (BMDMs), are the dominant immunological components of this niche, yet their precise roles in regulating metastasis remain poorly defined. Here, we sought to understand the interaction of DTCs with liver MΦ as they seed and colonize the liver. To model liver metastasis, mice received intraportal (iPo) injection of murine PDA cells with analysis 2 or 14 days later to examine metastatic seeding and outgrowth, respectively. Liver metastatic burden and immune cell populations were quantified by flow cytometry and immunohistochemistry. Liver MΦ were depleted using clodronate encapsulated liposomes (CEL) and KCs were depleted using Clec4fDTR mice administered diphtheria toxin. DTCs were found to interact with BMDMs more often than KCs during the seeding phase of metastasis. During colonization, KCs became excluded from metastatic colonies whereas BMDMs actively infiltrated. Although depletion of liver MΦ and KCs specifically did not affect metastatic seeding, MΦ depletion during the colonization phase inhibited metastatic colony outgrowth. Interestingly, BMDM infiltration into lesions was largely unaffected by CEL treatment, whereas KCs were uniformly depleted. This finding suggests that MΦ residing outside of metastatic lesions may be critical to supporting metastatic outgrowth. Supported by grants from NIH (T32 HL0439, F30 CA257287, R01 CA245323)