Abstract 6501: The SRG RAT supports in vivo human cell xenotransplantation through enhanced tumor microenvironment interactions

Abstract The use of immunodeficient mice for human tumor engraftment has proven to be an essential model of human cancer, with uses ranging from basic science to translational research. However, low engraftment rates, slow growth, and smaller tumor volumes can be limitations. Previously, we reported a highly immunodeficient rat strain developed by Hera BioLabs, with the functional deletion of both the Rag2 and Il2rg genes on the Sprague-Dawley background (SRG RAT®), which lacks B, T, and NK cells. We have shown that the SRG rat supports the growth of multiple PDX and CDX models, however, the mechanisms underlying the supportive growth are not fully understood. Additionally, direct comparison of tumor growth and the rates of engraftment between the SRG rat and NSG mice has remained limited. Here, we subcutaneously engrafted two CDX and five PDX models into SRG or NSG animals and tracked tumor growth. These models included prostate, lung, ovarian, and uterine cancer models. In all cases, the engraftment and tumor growth rates were better supported in the SRG rat compared to the NSG mouse. Interestingly, the SRG rat is not more immunocompromised than the NSG mouse, suggesting alternative mechanisms leading to the supportive growth in the SRG rat. To understand this, we explored potential differences in the tumor microenvironment (TME) between models grown in the two host animals. We analyzed tumors from the H660 CDX model of castrate-resistant prostate cancer grown in either SRG rats or NSG mice using markers of the TME via immunohistochemistry. This analysis showed differences in the vasculature and macrophages between the two host species. We complemented this analysis using Xenium in situ by 10X genomics to allow for single-cell spatial imaging of engrafted tumors. This analysis showed upregulation of the human CXCL2, LAMP3, and other genes in H660 tumors grown in the SRG rat vs the NSG mouse. Interestingly, high expression of these two genes has been linked to poor prognosis in cancer. Combined, our data demonstrate that the SRG rat supports the growth of multiple human cancer types and displays enhanced tumor microenvironment interactions compared to NSG mice. Citation Format: Caitlin M. O'Connnor, Diane Begemann, Kaitlin P. Zawacki, Kelsey Barrie, Fallon K. Noto, Grace Walton, Gabrielle H. Onishi, Jessica Durant, Taylor Branyan, Mike Schlosser, Goutham Narla. The SRG RAT supports in vivo human cell xenotransplantation through enhanced tumor microenvironment interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6501.