{
  "abstract": "Background Androgen deprivation therapy (ADT) is a cornerstone treatment for localized prostate cancer (PCa), particularly in patients with higher risk disease. While ADT improves survival, up to 40% of men undergoing therapy develop cardiovascular complications, making cardiovascular disease (CVD) the leading cause of death in this population. Recent prospective clinical data has shown a significant increase in coronary artery plaque in PCa patients receiving ADT compared to patients treated without ADT. However, there is a dearth of studies investigating the immunological landscape of this mortality. In non-cancer patients, systemic inflammation and immune dysregulation are prime contributors of coronary artery plaque formation and subsequent CVD. We, therefore, hypothesized that the cellular interactome of immune cells in coronary artery plaque following ADT could provide the mechanistic insight for CVD risk.Methods Mice with developed Myc-CAP prostate tumors were treated with leuprolide, the most prevalent ADT agent used in >90% of prostate cancer patients requiring ADT. Hearts were dissected and utilized for spatial transcriptomic using Visium HD. In parallel, longitudinal (baseline, month 3, 6, 12) plasma and PBMCs collected from men with localized PCa (N=25) receiving leuprolide were analyzed for adipocytokine array and immune phenotyping using flow cytometry.Results Leuprolide leads to plaque formation in mice having Myc-CAP prostate tumors. Notably, plaque size and severity score were higher in leuprolide-treated groups compared to untreated control, particularly in TLR9-treated and high-fat diet fed prostate tumor bearing-mice. Consistently, spatial transcriptomic analysis on leuprolide-treated cohort revealed an increased infiltration of inflammatory monocytes and T-cells within coronary plaque relative to control. Leptin signaling was enriched in these inflammatory monocytes following leuprolide treatment in both patients and mice. Further, we identified an increase in circulatory myeloid cells using flow cytometry, including classical/non-classical DC, intermediate monocytes and non-classical monocytes which indicated broad inflammatory nature of myeloid subset. We found an expansion of CD4+CD8+double-positive T-cells (known for inducing autoinflammation in graft-versus-host disease) having an exhausted stem-like phenotype, alongside a reduction in circulating total CD8+T-cells, including effector CD8+T-cells, highlighting T-cell centric impact of leuprolide for driving systemic inflammation-mediated CVD risk in primary prostate cancer patients.Conclusions ADT reshapes T-mediated immune response that causes systemic inflammation and can be a potential driver of CVD in primary PCa patients. To dissect the mechanisms underlining CVD risk, we plan to assess plaque formation propensity of myeloid cells present in primary PCa, explore the impact of a novel leptin inhibitor, and correlate these changes with angiographic coronary plaque progression.Ethics Approval Ethics approval was obtained from Emory IRB (ID: RAD5484-21) and Emory IACUC (Protocol number: 201700866)Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.",
  "authors": [
    {
      "affiliations": [
        "Emory University, Atlanta, GA, USA"
      ],
      "name": "Tuisha Gupta"
    },
    {
      "affiliations": [
        "Department of Hematology and Medical Oncology at Emory University, Atlanta, GA, USA"
      ],
      "name": "YuJie Chen"
    },
    {
      "affiliations": [
        "Department of Hematology and Medical Oncology at Emory University, Atlanta, GA, USA"
      ],
      "name": "Fanyuan Zeng"
    },
    {
      "affiliations": [
        "Department of Hematology and Medical Oncology at Emory University, Atlanta, GA, USA"
      ],
      "name": "Maggie Li"
    },
    {
      "affiliations": [
        "Department of Hematology and Medical Oncology at Emory University, Atlanta, GA, USA"
      ],
      "name": "Ganesh Talekar"
    },
    {
      "affiliations": [
        "Department of Pediatrics at Emory University, Atlanta, GA, USA"
      ],
      "name": "Hope Mumme"
    },
    {
      "affiliations": [
        "Winship Cancer Institute of Emory University, Atlanta, GA, USA"
      ],
      "name": "Gregory B Lesinski"
    },
    {
      "affiliations": [
        "Department of Hematology and Medical Oncology at Emory University, Atlanta, GA, USA"
      ],
      "name": "Edmund K Waller"
    },
    {
      "affiliations": [
        "Department of Pediatrics at Emory University, Atlanta, GA, USA"
      ],
      "name": "Manoj Bhasin"
    },
    {
      "affiliations": [
        "Department of Hematology and Medical Oncology at Emory University, Atlanta, GA, USA"
      ],
      "name": "Anant Mandawat"
    },
    {
      "affiliations": [
        "Department of Radiation Oncology at Emory University, Atlanta, GA, USA"
      ],
      "name": "Sagar Patel"
    },
    {
      "affiliations": [
        "Department of Hematology and Medical Oncology at Emory University, Atlanta, GA, USA"
      ],
      "name": "Kiranj Chaudagar"
    }
  ],
  "title": "770 Immune landscape of cardiovascular mortality in primary prostate cancer patients following leuprolide treatment, a non-canonical immunotherapy",
  "uid": "18545fb1-d21d-56e6-aa02-52eccabf6ffb"
}