Patient-Specific Vascularized Tumor Model: Blocking TAM Recruitment with Multispecific Antibodies Targeting CCR2 and CSF-1R.

Autor:	Nguyen HT; Department of Mechanical Engineering and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139 USA., Gurvich N; Marengo Therapeutics, 840 Memorial Dr, Cambridge, MA 02139 USA., Gillrie MR; Department of Mechanical Engineering and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139 USA.; Department of Medicine, University of Calgary, Calgary, AB, T2N 1N4 Canada., Offeddu G; Department of Mechanical Engineering and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139 USA., Humayun M; Department of Mechanical Engineering and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139 USA., Kan EL; Department of Mechanical Engineering and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139 USA., Wan Z; Department of Mechanical Engineering and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139 USA., Coughlin MF; Department of Mechanical Engineering and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139 USA., Zhang C; Marengo Therapeutics, 840 Memorial Dr, Cambridge, MA 02139 USA., Vu V; Department of Mechanical Engineering and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139 USA., Lee SWL; Department of Mechanical Engineering and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139 USA., Tan SL; Marengo Therapeutics, 840 Memorial Dr, Cambridge, MA 02139 USA., Barbie D; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA., Hsu J; Marengo Therapeutics, 840 Memorial Dr, Cambridge, MA 02139 USA., Kamm RD; Department of Mechanical Engineering and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139 USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Nov 29. Date of Electronic Publication: 2023 Nov 29.
DOI:	10.1101/2023.11.28.568627
Abstrakt:	Tumor-associated inflammation drives cancer progression and therapy resistance, with the infiltration of monocyte-derived tumor-associated macrophages (TAMs) associated with poor prognosis in diverse cancers. Targeting TAMs holds potential against solid tumors, but effective immunotherapies require testing on immunocompetent human models prior to clinical trials. Here, we develop an in vitro model of microvascular networks that incorporates tumor spheroids or patient tissues. By perfusing the vasculature with human monocytes, we investigate monocyte trafficking into the tumor and evaluate immunotherapies targeting the human tumor microenvironment. Our findings demonstrate that macrophages in vascularized breast and lung tumor models can enhance monocyte recruitment via TAM-produced CCL7 and CCL2, mediated by CSF-1R. Additionally, we assess a novel multispecific antibody targeting CCR2, CSF-1R, and neutralizing TGF-β, referred to as CSF1R/CCR2/TGF-β Ab, on monocytes and macrophages using our 3D models. This antibody repolarizes TAMs towards an anti-tumoral M1-like phenotype, reduces monocyte chemoattractant protein secretion, and effectively blocks monocyte migration. Finally, we show that the CSF1R/CCR2/TGF-β Ab inhibits monocyte recruitment in patient-specific vascularized tumor models. Overall, this vascularized tumor model offers valuable insights into monocyte recruitment and enables functional testing of innovative therapeutic antibodies targeting TAMs in the tumor microenvironment (TME). Competing Interests: Competing interests RDK discloses that he is co-founder and board member of AIM Biotech, and has research support from Amgen, AbbVie, Boehringer-Ingelheim, GSK, Novartis, Roche, Takeda, Eisai, Merck, KGaA, Visterra, and Marengo Therapeutics.
Databáze:	MEDLINE
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