{
  "abstract": "Background Pancreatic ductal adenocarcinoma (PDAC) remains a major challenge for immunotherapy due to its immunologically cold tumor nature, characterized by poor T cell infiltration and a highly suppressive tumor microenvironment. Here, we propose a novel strategy, combining fibroblast activation protein (FAP)-CD40 to activate dendritic cells (DCs) in the tumor microenvironment and programmed cell death protein-1 (PD1)-interleukin 2v (IL2v) to promote the expansion and differentiation of tumor-infiltrating T cells. We hypothesize that this combination will synergistically enhance both T cell priming and expansion directly within pancreatic 4662 KPC tumors, which recapitulate the immunologically cold features of human PDAC.Methods Immune cell distribution and abundance following FAP-CD40/PD1-IL2v monotherapy or combination therapy were analyzed using multiplexed confocal imaging (3D immune phenotyping). FTY720 studies assessed the contribution of lymph node priming in treatment efficacy, while CD4+/CD8+ T cell depletion experiments identified the roles of these subsets in combination therapy. T cell functionality was further assessed through ex vivo restimulation assays and single-cell RNA sequencing.Results Combination therapy induced dense intratumoral clusters of CD4 + and CD8+ T cells, colocalized with type 1 conventional DCs, termed as T cell-DC clusters (TDCs). These TDCs were strongly associated with tumor regression, which required both CD4+ and CD8+ T cells. Furthermore, T cells from combination-treated tumors showed enhanced functionality, with increased tumor necrosis factor-alpha and interferon-gamma production compared with monotherapy groups. Single-cell RNA sequencing revealed polarization of CD4+ T cells toward a T helper cell 1 phenotype in combination-treated tumors.Conclusion The combination of FAP-CD40 and PD1-IL2v offers a promising strategy for treating poorly infiltrated, cold tumors. By driving T cell infiltration, promoting de novo TDC formation and orchestrating local antitumor immunity, this strategy provides a foundation for future therapies targeting immunotherapy-resistant tumors.",
  "authors": [
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Thuy Trinh Nguyen"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Harold Gómez"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Mechthild Lutge"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Emilio Yángüez"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Tamara Hüsser"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Sina Nassiri"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Christine Trumpfheller"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Sara Colombetti"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Laura Codarri Deak"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Pablo Umaña"
    },
    {
      "affiliations": [
        "Institute of Experimental Immunology, Universität Zürich, Zürich, Switzerland",
        "Department of Immunology, Heidelberg University Medical Faculty Mannheim, Mannheim, Germany"
      ],
      "name": "Sònia Tugues"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Ines Grazina de Matos"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Leo Kunz"
    }
  ],
  "title": "FAP-CD40 and PD1-IL2v combination therapy reprograms immunologically cold tumors through de novo intratumoral T cell-dendritic cell clusters",
  "uid": "8d57cf24-960f-5c9e-be35-e31262049a9a"
}