{
  "abstract": "Background Humanized mice are highly valuable models for the preclinical development of cancer immunotherapies. However, conventional models often fail to mount robust and trackable tumor antigen-specific (TA-specific) T-cell responses, which hinders the comprehensive evaluation of therapies that depend on this endogenous antitumor immunity.Methods To address this limitation, we generated a humanized mouse model by engrafting immunodeficient mice with human hematopoietic stem cells that were transduced with predefined T-cell receptor (TCR) specificities. This approach enables the de novo generation of naïve, functional TA-specific T cells at adjustable frequencies.Results We found that transgene-bearing human thymocytes have a developmental advantage in the murine thymus, likely due to the early formation of the transgenic TCR and associated autonomous signaling. In tumor studies, the presence of these TA-specific T cells delayed tumor growth and promoted increased phenotypic diversity of intratumoral T cells, including the formation of PD-1 +/TCF1+ precursor exhausted T cells, which were absent in control mice. We demonstrate the utility of this model in two distinct therapeutic contexts. First, we found that high baseline frequencies of TA-specific T cells blunted the efficacy of a T-cell bispecific antibody (TCB), suggesting that pre-existing exhaustion limits TCB activity. Furthermore, the model enabled the evaluation of costimulatory agonists (FAP-CD40 and FAP-4-1BBL), and demonstrated their dependence on this T-cell compartment for antitumor efficacy.Conclusions This adaptable and physiologically relevant model provides a platform to dissect the complex interplay between human tumors, immune cells, and immunotherapies and has the potential to significantly improve the translation of preclinical findings to the clinic.",
  "authors": [
    {
      "affiliations": [
        "Roche Pharma Research and Early Development (pRED), Roche Innovation Center Zurich, Schlieren, Switzerland",
        "Institute of Experimental Immunology, University of Zurich, Zürich, Switzerland"
      ],
      "name": "Samuel Gebhardt"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development (pRED), Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Marine Le Clech"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Barbara Höllbacher"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development (pRED), Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Sarah Brunner"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development (pRED), Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Ahmet Varol"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development (pRED), Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Simone Lang"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development (pRED), Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Silvia Jenni"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development (pRED), Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Stefanie Briner"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development (pRED), Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Emilio Yángüez"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development (pRED), Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Tamara Hüsser"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development (pRED), Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Ioana Domocos"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development (pRED), Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Ria Tauscher"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany"
      ],
      "name": "Jan Eckmann"
    },
    {
      "affiliations": [
        "Institute of Experimental Immunology, University of Zurich, Zürich, Switzerland"
      ],
      "name": "Christian Münz"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development (pRED), Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Johannes Sam"
    }
  ],
  "title": "Precision modeling of tumor antigen-specific T-cell responses in humanized mice for preclinical assessment of cancer immunotherapies",
  "uid": "2eec0a0f-659c-5022-b537-ca81fb5423d3"
}