{
  "abstract": "Background CCR8 is a potential therapeutic target to treat cancer due to its role in the immunosuppression induced by regulatory T cells (Treg). The development of a physiologically relevant model to assess CCR8-targeting therapies depends, among others, on the maintenance of a proper interaction of the receptor and ligands. CCR8 has 2 ligands: CCL1 and CCL8. Mouse CCL8 induces specific calcium flux in human CCR8-transfected mouse cells, 1 suggesting that humanization of CCL8 is not mandatory. However, in vitro studies showed that murine CCL1 was unabled to interact with human CCR8. Lack of functional CCR8/CCL1 axis could have an impact on the suppressive activity of Treg cell, thus requiring the humanization of both CCR8 and CCL1. Herein, we describe a novel CCR8 and CCL1 double humanized model (genO-hCCR8/hCCL1).Methods Briefly, CCR8 and CCL1 were humanized. Both human genes are under the control of their endogenous mouse promoter, enabling physiological and regulated expression (no regulatory elements were altered by the gene editing process), which is key for the interpretation of the data obtained with the model.Results CCL1 is released in the serum from genO-hCCR8/hCCL1 mice. CCR8 is expressed on approximately half of the MC38 tumor infiltrated Tregs, enabling the activity of CCR8-targeting depleting antibodies, which induce tumor volume reduction (400mm 3 Vs. 750mm3) and increased survival (80% Vs. 30%) 20 days post MC38 inoculation. CCR8 expression is low/absent on Treg in the periphery (spleen, skin and blood), contrasting to the pattern of expression described in humans, and limiting the use of this model for safety assessment of CCR8-targeting therapies. Alternatively, expression of human CCR8 on human Treg shows a human-like pattern in genO-BRGSF-HIS mice, a model displaying functional human lymphoid and myeloid cells.2 CCR8 is expressed on Treg from blood and spleen, and CCR8-targeting depleting antibodies induced the depletion of Treg, suggesting that safety could be assessed in BRGSF-HIS mice. Assessment of CCR8-targeting antibodies remains to be tested in tumor bearing-genO-BRGSF-HIS mice.Conclusions Altogether, data suggest that genO-hCCR8/hCCL1 model is a valuable tool for CCR8-targeting agents efficacy assessment, enabling the investigation of immunomodulatory mechanisms at the tumor microenvironment. Nevertheless, this model has limitations to assess safety of CCR8-targeting compounds as the pattern of expression differs between human and mouse. The human-like expression pattern of CCR8 in naïve Treg from genO-BRGSF-HIS model makes it a more suitable model for safety and PD assessment.References Islam SA, et al. Mouse CCL8, a CCR8 agonist, promotes atopic dermatitis by recruiting IL-5+ T(H)2 cells. Nat Immunol. 2011 Feb;12(2):167–77.Martin GH, Gonon A, Martin-Jeantet P, et al. Myeloid and dendritic cells enhance therapeutics-induced cytokine release syndrome features in humanized BRGSF-HIS preclinical model. Front Immunol. 2024;15:1357716.",
  "authors": [
    {
      "affiliations": [
        "genOway, Lyon, France"
      ],
      "name": "Fabiane Sonego"
    },
    {
      "affiliations": [
        "genOway, Lyon, France"
      ],
      "name": "Angela Pappalardo"
    },
    {
      "affiliations": [
        "genOway, Lyon, France"
      ],
      "name": "Gaelle Martin"
    },
    {
      "affiliations": [
        "genOway, Lyon, France"
      ],
      "name": "Yacine Cherifi"
    },
    {
      "affiliations": [
        "genOway, Lyon, France"
      ],
      "name": "Patricia Isnard-Petit"
    },
    {
      "affiliations": [
        "genOway, Rhone Alpes, France"
      ],
      "name": "Kader Thiam"
    }
  ],
  "title": "443 Efficacy and safety assessment of CCR8-targeting agents in preclinical humanized models",
  "uid": "2a507eea-7906-5c45-89d0-2e21c4466993"
}