{
  "abstract": "Background Aging is the strongest independent risk factor for pancreatic ductal adenocarcinoma (PDAC) and is associated with worse clinical outcomes. As the global population ages, understanding how age-related changes impact tumor biology is critical. PDAC is characterized by a profoundly immunosuppressive tumor microenvironment (TME) and resistance to immune checkpoint inhibitors. However, the mechanisms by which aging shapes the TME and impairs antitumor immune responses remain poorly defined. We previously identified growth differentiation factor 15 (GDF-15), a cytokine highly secreted by aged pancreatic fibroblasts, as a promoter of PDAC progression. In this study, we investigated the contribution of aging-associated GDF-15 to immune suppression in PDAC.Methods We established orthotopic PDAC tumors using KPC and Panc02 cell lines in young (6-8-week-old) and aged (>52-week-old) syngeneic C57BL/6 mice. Tumors were harvested and analyzed using multiparameter flow cytometry, immunohistochemistry, and imaging mass cytometry to profile immune and stromal cell populations. Functional studies involved administration of recombinant GDF-15 to young mice and genetic knockout of GDF-15 in aged mice to assess effects on tumor growth and immune composition.Results Tumors in aged mice demonstrated accelerated growth and increased liver metastases compared to tumors in young mice. The aged TME exhibited reduced infiltration of cytotoxic CD8 + T cells, decreased classical dendritic cells (cDCs), increased FoxP3+ regulatory T cells, a reduction in antigen-presenting cancer-associated fibroblast (CAF) cells. Administration of recombinant GDF-15 to young mice suppressed CD8+ T cell infiltration and partially mimicked the immune landscape observed in aged hosts. Conversely, aged GDF-15 knockout mice developed significantly smaller tumors and displayed improved CD8+ T cell infiltration compared to age-matched wild-type controls, indicating a direct role for GDF-15 in shaping the immunosuppressive aged TME.Conclusions Our findings demonstrate that aging alters the PDAC immune microenvironment in a manner that promotes immune evasion and tumor progression. GDF-15, elevated in aged stroma, contributes to these effects by suppressing CD8 + T cell infiltration and altering CAF phenotypes. These data uncover a novel mechanism of age-associated immune suppression in PDAC and provide a strong rationale for targeting GDF-15 to enhance antitumor immunity in older patients. This work supports the broader concept that age-related stromal remodeling is a critical, targetable barrier to effective immunotherapy in PDAC.Ethics Approval Animal studies were approved by the Johns Hopkins University ACUC in protocol M025M148",
  "authors": [
    {
      "affiliations": [
        "Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Emma Kartalia"
    },
    {
      "affiliations": [
        "Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "James M Leatherman"
    },
    {
      "affiliations": [
        "Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Sara Young"
    },
    {
      "affiliations": [
        "Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Edwin Y He"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Elizabeth M Jaffee"
    },
    {
      "affiliations": [
        "Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Won Ho"
    },
    {
      "affiliations": [
        "Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Saumya Maru"
    },
    {
      "affiliations": [
        "Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Daniel J Zabransky"
    }
  ],
  "title": "1275 Aging-associated GDF-15 expression drives immune suppression in pancreatic cancer",
  "uid": "a4152de6-5515-5b84-9ca7-0906d4ecafe4"
}