{
  "abstract": "Background From the first use of an immunomodulatory agent in clinical studies to modern immunotherapies, these were mainly focused on modulating adaptive immune response. However, only a fraction of patients can respond to these treatments, and the complexity of the tumor microenvironment requires other players to be targeted. γδ T cells are unconventional T cells, as they recognize antigens mostly in a MHC-unrestricted fashion. They show a high diversity of effector functions, from cytotoxicity to mediators’ production and wound healing. Their preactivated state allows a quick immune response, and their role in tumor development, both in beneficious or deleterious manner, were demonstrated in numerous types of cancer. While preliminary results are promising, investigation of such therapies in preclinical models is challenging, because γδ T cells are not developed at satisfactory levels in most of the humanized mouse models.Methods Here we describe the presence, the functionality and the recruitment of γδ T cell in genO-BRGSF (Balb/C Rag2 -/-, IL2Rγ-/-, SIRPαNOD and Flt3-/-) mice reconstituted with human cord blood CD34+ cells (genO-BRGSF-HIS). These mice develop functional lymphoid and myeloid compartments, this engraftment is stable for over a year1 and mice do not develop GvHD.Results At steady-state, genO-BRGSF-HIS mice show a diverse population of γδ T cells in their blood and peripheral organs, expressing Vd1, Vd2 or Vd3 chains, although their ratio is different in blood from genO-BRGSF-HIS mice and human PBMC. These cells can be expanded using zoledronate with human IL-2, allowing ex vivo or in vivo assays for γδ T cells targeting compounds. This specific activation, as well as the activation with a Vd1-targeting agent, leads to an increase in γδ T cells activation state (expression of CD25, CD69, CD137) and their effector function (cytokine production or CD107a-associated degranulation). Similarly, an ‘Expander’ targeting Vγ9 significantly increased Vγ9 expressing cells frequencies, and serum levels of perforin and IFN-γ in treated mice. Interestingly, γδ T cells were recruited into the tumor microenvironment of the triple negative breast cancer line MDA-MB-231, where majority of the γδ T cells are Vd1, and show an activated status based on the expression of CD107a. These data suggest that therapies designed to expand and activate γδ T cells could be assessed in genO-BRGSF-HIS tumor bearing mice.Conclusions Therefore, the development of functional γδ T cells in genO-BRGSF-HIS mice brings a new perspective on the assessment of therapies targeting this cell population in humanized mouse models.Reference Labarthe L, Henriquez S, Lambotte O, et al. Frontline science: exhaustion and senescence marker profiles on human T cells in BRGSF-A2 humanized mice resemble those in human samples. J Leukoc Biol. 2020;107(1):27–42.",
  "authors": [
    {
      "affiliations": [
        "geOway, Lyon, Rhône-Alpes, France"
      ],
      "name": "Florent Creusat"
    },
    {
      "affiliations": [
        "geOway, Lyon, Rhône-Alpes, France"
      ],
      "name": "Siham Hedir"
    },
    {
      "affiliations": [
        "geOway, Lyon, Rhône-Alpes, France"
      ],
      "name": "Alexis Gonon"
    },
    {
      "affiliations": [
        "geOway, Lyon, Rhône-Alpes, France"
      ],
      "name": "Amelie Marguier"
    },
    {
      "affiliations": [
        "geOway, Lyon, Rhône-Alpes, France"
      ],
      "name": "Yacine Cherifi"
    },
    {
      "affiliations": [
        "geOway, Lyon, Rhône-Alpes, France"
      ],
      "name": "Fabiane Sonego"
    },
    {
      "affiliations": [
        "geOway, Lyon, Rhône-Alpes, France"
      ],
      "name": "Gaelle Martin"
    },
    {
      "affiliations": [
        "geOway, Lyon, Rhône-Alpes, France"
      ],
      "name": "Kader Thiam"
    }
  ],
  "title": "835 γδ T cells are functional and recruited into the TME in genO-BRGSF-HIS mice",
  "uid": "9dfaf1c4-ae1d-55ba-afd7-c1d80176dda6"
}