The SRG RAT supports human cell xenotransplantation through enhanced tumor microenvironment interactions

Abstract

The use of immunodeficient mice for human tumor engraftment is 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 with the functional deletion of both the Rag2 and Il2rg genes on the Sprague-Dawley background (SRG RAT(R)), which lacks B, T, and NK cells. Here, we subcutaneously engrafted two cell-derived xenograft (CDX) and seven patient-derived xenograft (PDX) models, including prostate, lung, ovarian, and uterine cancer models, into the SRG rat or NSG mouse models and tracked tumor growth. 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. Therefore, we explored potential differences in the tumor microenvironment (TME) between models grown in the two host animals. Lung PDX models grown in SRG rats showed enhanced formation of vasculature and stroma and were morphologically more consistent with the originating patient tumors. IHC analysis of the NCI-H660 CDX model showed differences in the tumors stroma, vasculature, and macrophages when grown in the two host species. Single-cell spatial imaging of engrafted tumors showed upregulation of the human CXCL2 and TCIM in NCI-H660 tumors grown in the SRG rat versus the NSG mouse, both of which have 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.