Abstract 2949: Sprague-Dawley Rag2 null Il2rgamma null SRG rat (OncoRat®) has enhanced tumor microenvironment in human prostate cancer xenografts
Authors: Begemann Diane , Adedeji Bisoye Towobola , Steffey Valeriya , Moody Sam , Narla Goutham , Noto Fallon 
Published: July 2021

Human tumor xenografts are a staple tool for understanding tumor biology, growth kinetics, and therapeutic efficacy. While these studies are most commonly done in immunocompromised mice, we have created a Sprague Dawley Rag2 null, Il2rgamma null SRGTM rat that is an excellent host for human xenografts (OncoRat®). Lacking B, T, and NK cells, the SRG rat readily supports the growth of multiple human cancer cell lines, including lines that do not engraft well or grow consistently in existing mouse models. The tumor microenvironment (TME) is a critical factor for supporting xenograft tumors, and the microenvironment of a human tumor grown in the rat has yet to be fully characterized. In this study, a collaborative effort between research institutions discovered that the tumor microenvironment in the SRG rat is more robust, involved, and more supportive of human tumor growth than in NSG mice. To characterize the aforementioned differences in rat and mouse TME, human prostate cancer cell lines LNCaP and VCaP were grown in NSG mice and SRG rats. Formalin fixed paraffin embedded sections were stained via immunohistochemistry (IHC) for both rat and mouse tumor microenvironment markers. Collagen marker CD29, endothelial cell marker CD31, macrophage marker CD45, smooth muscle actin, and stromal markers CD54 and vimentin were analyzed in both animal hosts. When applicable, staining was quantified via counting positive cells per high powered field of view. When VCaP and LNCaP xenograft tumors are hosted by SRG rats, the host TME is significantly more involved within the human tumor, and readily supports tumor growth. Comparing the same markers in SRG rat and NSG mouse hosts revealed a stark difference - the SRG rat TME is more prevalent than the mouse. Results show significantly increased stromal cells per high powered field in the SRG rat when compared to tumors of the same cell line grown in the NSG mouse. There is heavily increased endothelial and stromal cell infiltration from the host into the human tumor, and higher heterogeneity within the cell population in tumors hosted by SRG rats. These data show that there are more human tumor epithelial cell interactions within the TME of the SRG rat than in NSG mouse. Increased stromal involvement more accurately recapitulates a human TME and may help explain the better take rates and faster growth rates of xenografts in SRG rats versus NSG mice. It is well known that recapitulating the tumor cell population heterogeneity is a study limitation when using animal models. Utilization of the SRG rat TME has great value in nonclinical research by more accurately translating into human disease, while remaining in a readily available immunodeficient animal model (i.e., OncoRat).

Citation Format: Diane Begemann, Bisoye Towobola Adedeji, Valeriya Steffey, Sam Moody, Goutham Narla, Fallon Noto. Sprague-Dawley Rag2 null Il2rgamma null SRG rat (OncoRat®) has enhanced tumor microenvironment in human prostate cancer xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2949.