A syngeneic renal cancer mouse model for the discovery of novel immuno-oncology therapies
11 / 18 / 2020
We have fully set up and characterized a syngeneic Renca renal mouse model recapitulating most of the human RCC condition features. Indeed, our model diplays an enriched tumor microvascular environment and relatively low immune infiltration - nevertheless constituted of a strong Myeloid-Derived Suppressor Cells (MDSCs) proportion, which cells serving as pivotal factors of tumor-induced Th2 response, subsequent escape and further promotion of angiogenesis. Furthermore and as in patients, the model shows an accumulation of circulating MDSCs. Interestingly, sunitinib, first-line anti-angiogenic therapy for RCC, leads here to a tumor growth inhibition, an effect seemingly mediated by a tumor vascular normalization and a decline in circulating MDSCs, which correlates with a potentially improved peripheral T cell response.
Renal Renca tumor model: preclinical efficacy of sunitinib
Figure 1: Renal Renca syngeneic tumor model - as a model of renal malignancies known as angiogenesis-dependent – displays a great sensitivity to Sunitinib. Individual tumor volume (mm3) (A) and Kaplan-Meier plot survival (B) of Renca tumor-bearing mice upon vehicle and sunitinib treatment. Renca tumors are significantly responsive to the antiangiogeneic agent. The response amplitude to sunitinib still offers enough range to evaluate strategies including e.g. vascular stabilizing agents, hypoxia regulators, immune checkpoint blockers, and immune modulators targeting immunosuppressive subpopulations.
Sunitinib induces a reduction of tumor vasculature in Renca tumor model
Figure 2: Sunitinib induces tumor vessel density reduction & normalization in Renca tumors.
Renca tumor-bearing mice were treated with vehicle or sunitinib. At the end of treatment, tumors were collected and processed for CD31 (red, blood vessels) and NG2 (cyan, pericytes) immunohistofluorescence and image acquisition & analysis. (A) Representative images of CD31 and NG2 immunostaining. (B) CD31 vessel density is analyzed and presented as a percentage per total sectional area (a), while pericyte coverage is analyzed and presented as a percentage of NG2 and CD31 colocalization (b).
Sunitinib-mediated efficacy is underpinned by a decline in circulating MDSCs and peripheral T cell increase
Figure 3: Multiparametric flow cytometry-based analysis of blood T cells and myeloid cell subsets of Renca tumor-bearing mice upon vehicle, and sunitinib treatment.
Upon sunitinib treatment, blood FACS analysis interestingly shows an important decrease of circulating CD11b myeloid cells and MDSCs, which correlates with a potentially improved peripheral T cell response as underlined by the increase in the CD3, CD4, and CD8 T cell populations.