401 genO-hCCR8/hCCL1/hFcγR preclinical mouse model for efficacy assessment of CCR8-targeting agents
Year: 2026
Type: conference-abstract
Abstract: Background CCR8 is an emerging therapeutic target in oncology due to its role in Treg-mediated immunosuppression. The development of physiologically relevant preclinical models to evaluate CCR8-targeting therapies requires preservation of functional interactions between the receptor and its ligands. CCR8 has two known ligands, CCL1 and CCL8. Previous studies have shown that mouse CCL8 can induce calcium flux in human CCR8-transfected murine cells, 1 suggesting that humanization of CCL8 may not be required. In contrast, murine CCL1 does not interact with human CCR8 in vitro, indicating that disruption of the CCR8/CCL1 axis may impair Treg suppressive function and necessitate humanization of both CCR8 and CCL1. In addition, depletion of CCR8+ Tregs by therapeutic agents has been shown to depend on Fcγ receptor (FcγR) engagement.2 However, significant interspecies differences in FcγR repertoire and expression patterns between mice and humans limit the translational relevance of mouse models expressing mouse FcγR. A previously described humanized FcγR mouse model expressing human FcγRI, FcγRIIA, FcγRIIB, FcγRIIIA, and FcγRIIIB in a human-like distribution enables more accurate evaluation of Fc-mediated immune responses.3 Building on this, we developed a novel humanized model expressing humanized CCR8, CCL1, and FcγRs (genO-hCCR8/hCCL1/FcγR).Methods CCR8 and CCL1 were humanized by replacing the murine genes with their human counterparts under the control of endogenous mouse promoters. This strategy preserves physiological regulation of gene expression, as no regulatory elements were altered during gene editing. The resulting genO-hCCR8/hCCL1 model was subsequently crossed with the genO-hFcγR model to generate the triple-humanized genO-hCCR8/hCCL1/FcγR strain.Results Expression and functionality of the CCR8/CCL1 axis were confirmed: Circulating human CCL1 was detected in the serum of genO-hCCR8/hCCL1 mice. CCR8 expression was observed on tumor-infiltrating Tregs in the MC38 model, enabling evaluation of CCR8-targeting depleting antibodies. Treatment resulted in significant antitumor activity, with reduced tumor volume and improved survival at 20 days post-inoculation. However, CCR8 expression on Tregs in peripheral tissues (spleen, skin, and blood) was low or absent, differing from the expression pattern observed in humans and limiting the utility of this model for safety assessment. In the genO-hCCR8/hCCL1/FcγR model, MC38 tumors established successfully, and studies evaluating efficacy and mechanism of action of CCR8-targeting agents are ongoing.Conclusions The genO-hCCR8/hCCL1 model represents a valuable platform for assessing the efficacy of CCR8-targeting therapies and investigating immunomodulatory mechanisms within the tumor microenvironment. The addition of humanized FcγRs in the genO-hCCR8/hCCL1/FcγR model further enhances translational relevance by enabling evaluation of Fc-mediated effector functions.References Islam SA, Chang DS, Colvin RA, Byrne MH, McCully ML, Moser B, Lira SA, Charo IF, Luster AD. Mouse CCL8, a CCR8 agonist, promotes atopic dermatitis by recruiting IL-5 + T(H)2 cells. Nat Immunol. 2011;12:167–177.Campbell JR, McDonald BR, Mesko PB, Siemers NO, Singh PB, Selby M, Sproul TW, Korman AJ, Vlach LM, Houser J, Sambanthamoorthy S, Lu K, Hatcher SV, Lohre J, Jain R, Lan RY. Fc-optimized anti-CCR8 antibody depletes regulatory T cells in human tumor models. Cancer Res. 2021;81:2983–2994.Van Damme KFA, Sichien D, Van der Borght K, Van Moorleghem J, Van Gassen S, Jorssen J, De Winter S, De Leeuw E, Wang C, Chai Q, Brotcke Zumsteg A, Schmid MA, Bosteels V, De Bleser P, Vanheerswynghels M, De Prijck S, Bujko A, De Nolf C, Schuijs MJ, Van Den Eeckhout B, Rogiers I, Browaeys R, Thielemans F, Quintelier K, D’Hont J, Hochepied T, Isnard Petit P, Augier S, Courtois R, Verwaerde S, Vanhee S, Schetters S, Scott CL, Aerts S, Saeys Y, Korman AJ, Benigni F, Corti D, Janssens S, Vandamme N, Baptista AP, Desmet C, Elewaut D, Hammad H, Morel A, Vivier E, Sônego F, Thiam K, Voet S, Balbino B, Lambrecht BN. Cross-species cellular mapping and humanization of Fcγ receptors to advance antibody modeling. Sci Immunol. 2026;11:eady7328.Ethics Approval All animal experimental procedures were ethically approved by the ethical committee VetAgro Sup n°018, validated by the French Ministry of Education and Research (APAFiS #38722) and performed in line with relevant guidelines and regulations including the EU Directive 2010/63/EU, the related French deícret n° 2013-118, and the 3Rs (Refinement, Reduction, Replacement).
Institution: Genoway (France)
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225177384