Abstract 4139: Functional human myeloid cells in BRGSF-HIS humanized mice enables myeloid-directed therapy assessment

Abstract

Translational preclinical assessment of myeloid-targeting therapies is considered challenging due to the reduced availability of humanized mouse models expressing both lymphoid and myeloid compartments. Most of the humanized models harboring myeloid compartment overexpress human cytokines, leading to body weight loss, anemia and a short life span. Recent report described the BRGSF-HIS as an alternative model displaying all major human hematopoietic cell subsets, such as B, T, natural killer (NK), dendritic cells (DCs), plasmacytoid cells (pDCs) and monocytes/macrophages. Human myeloid cells developed in the BRGSF-HIS mice without side effects and human immune system engraftment is stable for over a year (Labarthe et al., 2019), favoring long terms studies with agents requiring a wide therapeutic window. Here we report that myeloid compartment developed in BRGSF-HIS mice is recruited in the tumor microenvironment of tumor bearing mice, and are also capable of triggering effector mechanisms such as ADCP and ADCC. Myeloid cells developed in the BRGSF-HIS mice are functional as, ex vivo stimulation with TLR and STING agonists induce CD83 expression and pro-inflammatory cytokine secretion (TNF-α, IL-1β, CCL2, ⋯) by monocytes and bone marrow derived macrophages (BMDM). In vivo, myeloid cells are activated through LPS challenge, leading to increased CD83-expressing cDCs frequency and CD83 and CD86 expression levels. Furthermore, BMDM are efficiently skewed toward M1 and M2-like profiles in response to LPS and IL-4, respectively. Analyses of TME from MDA-MB-231, show the recruitment of human immune cells, including T cells, NK cells, cDC and activated M2 macrophages (expressing both CD86 and CD206). Expression of FcγR, essential for antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP) activities, is found on human peritoneal macrophages and BMDM from BRGSF-HIS. ADCP activity mediated by macrophages was established as tumor cells are specifically phagocyted ex vivo in presence of a bispecific antibody (anti-human CD47 x tumor-associated antigen). Such findings were corroborated by B cell depletion in vivo induced by Rituximab (anti-CD20 mAb - hIgG1), which has been described to trigger CDC, ADCC and ADCP via FcγR (Teige et al., 2019). Finally, OKT3 induces cytokine release syndrome in these mice, evidenced by cytokine release, body weight and temperature drop. Treatment with Infliximab reduced these symptoms, suggesting that BRGSF-HIS mice enable assessment of safety and its clinical management. In summary, BRGSF-HIS mice develop myeloid cells without side effects and has a wide therapeutic window, enabling the assessment of effector mechanisms such as ADCP and ADCC, triggered by of myeloid-targeted therapies. Citation Format: Florence Renart-Depontieu, Gaëlle Martin, Valery Moine, Coline Burnet-Merlin, Florent Creusat, Alexis Gonon, Perrine Martin-Jeantet, Fabiane Sônego, Lise Nouveau, Yacine Cherifi, Kader Thiam. Functional human myeloid cells in BRGSF-HIS humanized mice enables myeloid-directed therapy assessment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4139.