Colorectal cancer is the third most prevalent cancer worldwide and the second-leading cause of cancer-related mortality. 85% of colorectal cancer patients have a microsatellite stable (MSS) phenotype and thus do not benefit from currently available immunotherapies. Thus, there is a need to develop preclinical models that recapitulate the human tumor-immune microenvironment and allow meaningful testing of novel immunotherapies and combination treatments. MSS colorectal cancers have been shown to be frequently infiltrated with immunosuppressive macrophages, and these tumor-infiltrating macrophages have been shown to enhance tumor progression by stimulating angiogenesis and suppressing antitumor immune responses, and to promote therapy resistance and metastasis.
Recently, two next-generation mouse models, NSG-Quad and MISTRG-6, have been developed, which express human cytokines that support the development of a diverse and functional human immune system as well as human tumor growth (Review: https://doi.org/10.3390/cancers15112989). Understanding model-specific differences, particularly with respect to human tumor-infiltrating macrophages, is key for faithful modeling of the human tumor-immune microenvironment and for meaningful preclinical testing of cancer immunotherapies.
In this study, we demonstrate that both NSG-Quad and MISTRG-6 develop human macrophages that infiltrate human colorectal cancers. However, MISTRG-6 show a higher number of immunosuppressive tumor-infiltrating macrophages resulting in increased tumor growth compared to NSG-Quad. In addition, NSG-Quad have an impaired development of T lymphocytes and natural killer cells, and frequently develop a macrophage hyperactivation syndrome.
These results provide important insights into the dynamics of the human tumor-immune microenvironment in NSG-Quad and MISTRG-6, and demonstrate that MISTRG-6 is a valuable model for immuno-oncology studies and preclinical therapeutic testing. In a next step, we will use MISTRG-6 and patient-derived tumors to investigate the efficacy of different macrophage-targeted therapies in MSS colorectal cancer.
This research was supported by the “International PhD Program in Translational Oncology” – IPPTO (Austrian Science Fund, FWF), the Austrian Academy of Sciences, the Vienna Science and Technology Fund (WWTF) and the Fellinger Cancer Research Foundation.
Publication:
Molecular Therapy Methods & Clinical Development
Comparison of NSG-Quad and MISTRG-6 humanized mice for modeling circulating and tumor-infiltrating human myeloid cells
Anna Chen*, Viktoria Knöbl*, Oliver Walzer, Jana Hauser, Ines Neuwirth, Magdalena Frank, Nina Braun, Semina Duvnjak, Johannes Reisecker, Carmen Stecher, Alex Farr, Christine Brostjan, Dietmar Herndler-Brandstetter