{
  "abstract": "Background Metastasis is the major cause of death in cutaneous melanoma. Melanoma is a disease of aging. The median age of diagnoses for melanoma is 65 years old, and incidence, metastasis, and mortality are significantly associated with age. Despite this, pre-clinical studies predominantly focus on young (8-week-old) mouse models, which don’t properly recapitulate the metastatic tissue microenvironment (TME) in patients.Previously, our lab has shown that the aged lung (12-16 months) promotes metastatic melanoma outgrowth, while the young lung (8-12 weeks) promotes dormancy. We further found that reactivated melanoma cells in the aged lung secrete high levels of Protein S1 (PROS1), which induced further progression. These studies did not focus on other common metastatic sites such as the liver and did not look at the immune system. We have since optimized an innovative method of liver colonization, hydrodynamic tail vein (HDTV), and have discovered that the aged liver significantly increases outgrowth relative to young. Investigation of the immune system via flow-cytometry allowed us to identify a distinct myeloid population (CD11B+) that expresses high levels of Arginase 1 (ARG1), which is increased in healthy aged pre-metastatic lung and liver and is further increased following metastasis. We hypothesized that its increase in the aged TME is significant as it may play a role in allowing outgrowth of proliferative cells, unabated by the immune system.Methods To investigate how Arg1 enables metastatic progression in a growth restrictive metastatic TME, we treated C57BL/6 young male mice with recombinant Arg1 (HY-P71833, 100ug/mL) via intraperitoneal injection (IP) injection while aged mice were treated with an inhibitor of ARG1, Numidargistat (CB-1158, 100 mg/kg/mouse), given via oral gavage twice daily. To investigate the immune mediated effects of PROS1 in the lung and liver, we overexpressed it in melanoma cells prior to injection into young mice.Results Recombinant ARG1 significantly increased metastatic lung and liver outgrowth in young mice, while simultaneously decreasing NK cells. ARG1 inhibition in aged mice decreased outgrowth and increased NK cell infiltration into both tissues. PROS1 overexpression also significantly increased metastatic colonization across both tissues and increased myeloid specific expression of ARG1.Conclusions This provides strong evidence that age induced pre-metastatic increase in Arg1 myeloid cells, coupled with secretion of PROS1 from reactivated melanoma cells in the aged metastatic lung and liver provides two mechanisms in which age-mediated progression can drive a potentially immunosuppressed TME phenotype to promote efficient metastatic outgrowth in elderly patients.Ethics Approval This study followed the tenets of the Declaration of Helsinki and was approved by our institutional research ethics committee (Fox Chase Cancer Center, Philadelphia, USA; protocols #23-05; OLAW #D16-00184).",
  "authors": [
    {
      "affiliations": [
        "Fox Chase Cancer Center, Philadelphia, PA, USA",
        "Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA"
      ],
      "name": "Jhon Steven Pasamonte"
    },
    {
      "affiliations": [
        "Fox Chase Cancer Center, Philadelphia, PA, USA"
      ],
      "name": "Kelly Coutant"
    },
    {
      "affiliations": [
        "Fox Chase Cancer Center, Philadelphia, PA, USA"
      ],
      "name": "Christopher Price"
    },
    {
      "affiliations": [
        "Fox Chase Cancer Center, Philadelphia, PA, USA"
      ],
      "name": "Anastasiia Burtseva"
    },
    {
      "affiliations": [
        "Fox Chase Cancer Center, Philadelphia, PA, USA",
        "Temple University, Philadelphia, PA, USA"
      ],
      "name": "Pulkit Datt"
    },
    {
      "affiliations": [
        "Fox Chase Cancer Center, Philadelphia, PA, USA"
      ],
      "name": "Mitchell Fane"
    }
  ],
  "title": "1145 The role of Arginase 1 in immune infiltration in the pre-metastatic tumor microenvironment",
  "uid": "de6321d3-1a87-540e-919c-5a98dfd2e068"
}