{
  "abstract": "Background The clinical success of immuno-oncology (IO) agents is often limited by the immunosuppressive tumor immune microenvironment (TIME), which is poorly recapitulated by traditional preclinical models, leading to poor predictive value for therapeutic efficacy. Tumor-associated macrophages (TAMs) are key players in establishing this immunosuppressive niche. To address this gap, we developed a high-fidelity 3D vascularized immunosuppressive tumor model on a microphysiological system (MPS) platform for more accurate, clinically relevant evaluation of IO drug candidates.Methods Our MPS platform was used to engineer a multicomponent 3D tumor model with patient-derived organoids (PDOs) for tumor heterogeneity, co-cultured with endothelial cells and fibroblasts to form a perfusable vascular network. An immunosuppressive TIME was created by introducing human monocytes through the vasculature. Monocyte differentiation into M2-like macrophages was validated via flow cytometry, and the immunosuppressive secretome was confirmed by multiplex analysis. To validate the model, we compared the efficacy of a T-cell engager (TCE) bispecific antibody (CD3×EpCAM) in models with and without macrophages, using breast cancer PDOs. Tumor killing was quantified by imaging and T-cell activation by cytokine release.Results A robust, pathophysiologically relevant 3D model with a perfusable vascular network and PDO-driven heterogeneity was established ( figure 1). Immunofluorescent imaging and flow cytometry revealed monocytes introduced via the vasculature transmigrated and differentiated into immunosuppressive macrophages, fostering a pro-tumoral cytokine milieu. Immunofluorescent image analysis showed that while the T-cell engager effectively killed tumors in the absence of macrophages, its anti-tumor activity was significantly diminished when macrophages were present. This reduction in efficacy, evidenced by less tumor lysis and attenuated T-cell activation, demonstrates the model’s ability to recapitulate macrophage-mediated immune suppression.Conclusions Our MPS-based platform models a vascularized, immunosuppressive TIME that functionally impairs T-cell-based immunotherapies, thus avoiding overestimation of efficacy. By showing that macrophages attenuate TCE efficacy, we have validated a powerful preclinical tool ( figure 2). This model enables investigation of mechanisms of immunosuppression, testing of novel IO agents, and design of combination strategies to overcome immunosuppressive barriers in solid tumors, ultimately improving the clinical translation of new cancer treatments.Abstract 1271 Figure 13D immunosuppressive tumor model with perfusable vasculature and macrophagesAbstract 1271 Figure 2T cell engager (CD3 × EpCAM) efficacy testing in an immunosuppressive TNBC vTIME model",
  "authors": [
    {
      "affiliations": [
        "Qureator Inc., San Diego, CA, USA"
      ],
      "name": "Junfeng Wang"
    },
    {
      "affiliations": [
        "Qureator Inc., San Diego, CA, USA"
      ],
      "name": "Byungjun Lee"
    },
    {
      "affiliations": [
        "Qureator Inc., San Diego, CA, USA"
      ],
      "name": "Delaney Donnelly"
    },
    {
      "affiliations": [
        "Qureator Inc., San Diego, CA, USA"
      ],
      "name": "Jihye Baek"
    },
    {
      "affiliations": [
        "Qureator Inc., San Diego, CA, USA"
      ],
      "name": "Bushra Rajput"
    },
    {
      "affiliations": [
        "Qureator Inc., San Diego, CA, USA"
      ],
      "name": "Hyeon Geun Park"
    },
    {
      "affiliations": [
        "Qureator Inc., San Diego, CA, USA"
      ],
      "name": "Emily Yunha Shin"
    },
    {
      "affiliations": [
        "Qureator Inc., San Diego, CA, USA"
      ],
      "name": "Aneesh Sathe"
    },
    {
      "affiliations": [
        "Qureator Inc., San Diego, CA, USA"
      ],
      "name": "Tsung-li Liu"
    },
    {
      "affiliations": [
        "Qureator Inc., San Diego, CA, USA"
      ],
      "name": "Branka Mitrovic"
    },
    {
      "affiliations": [
        "Qureator Inc., San Diego, CA, USA"
      ],
      "name": "Kyusuk Baek"
    },
    {
      "affiliations": [
        "Qureator Inc., San Diego, CA, USA"
      ],
      "name": "Sanghee Yoo"
    }
  ],
  "title": "1271 A clinically relevant 3D immunosuppressive tumor model with perfusable vasculature demonstrates macrophage mediated impairment of immunotherapy",
  "uid": "cc639f7e-5fc6-5f22-9331-b7473430f700"
}