Abstract B074: Enhanced anti-tumor response to anti-angiogenic/hypoxia-regulating therapies in combination with immune checkpoint blockade in a murine model of renal carcinoma

Abstract Background: While antiangiogenic & other targeted therapies have been shown effective in preclinical & clinical trials, tumors can acquire resistance thereby conferring them the ability to survive and grow under hypoxic conditions. Hence, combining angiogenesis- and/or hypoxia-targeted strategies with immune checkpoint inhibitors (anti-PD1/PDL1) are of particular interest as these approaches might overcome resistance or enhance the immune system's ability to attack tumor cells. Methods: Using the murine syngeneic RENCA tumor model, this study investigated the effects of an antiangiogenic strategy (using sunitinib) and a hypoxia-regulating agent (using Everolimus as a mTOR inhibitor), each alone and in combination, in the presence and absence of PD1/PDL1 blockade. In vivo anti-tumor effects were investigated on tumor growth and survival. Blood & tumor samples were immunoprofiled by flow cytometry. In addition, immune cell infiltrate, hypoxia, and vascular density within the tumor were assessed by multiplexed immunohistofluorescence. Results: As expected, sunitinib triggered tumor growth delay which was not optimized upon combination with anti-PD1/PDL1 agents. While sunitinib did not induce major modulation of the tumor immune infiltrate, its effectiveness was underpinned by the reduction of vascular density and peripheral immune modulation resulting in increased T cells and a decline in MDSCs. Everolimus was also found to decrease tumor burden, which was associated with a decrease and an increase of circulating MDSCs and T cells, respectively. Its anti-tumor activity was optimized upon sunitinib combination, an effect associated with enhanced increase of peripheral CD8 T cells and decrease of MDSCs. However, combining everolimus with PDL1 blockade improved tumor growth inhibition and survival compared to each agent alone, without major immunomodulatory activity. Interestingly, treatment with all three agents together effectively slowed tumor growth resulting in better survival compared to each combo- (except everolimus/anti-PDL1) and monotherapy. This effect was associated with increased CD8 T cells and decreased MDSCs in the periphery. At the tumor level, a decrease in myeloid cells and MDSCs and a trend towards increased T infiltrate were observed. Conclusion: This study confirms the efficacy of sunitinib and everolimus in the renal tumor model likely underpinned by sunitinib-induced hypoxia that enhances the activity of everolimus, which in turn synergizes with sunitinib. Beyond this, the data highlight the efficacy of sunitinib/everolimus/anti-PDL1 tri-therapy all leading to strong tumor regression, suggesting a potential role of PDL1 blockade in this response which may further promote lymphocyte mobilization and their infiltration in an environment where angiogenesis and hypoxia are not exaggerated. Therefore, further explorations in a view to optimizing treatment regimens to best improve the effects of each agent and facilitate their synergy are warranted. Citation Format: Assia Chaibi, Christophe Rey, Alban Bessede, Imane Nafia. Enhanced anti-tumor response to anti-angiogenic/hypoxia-regulating therapies in combination with immune checkpoint blockade in a murine model of renal carcinoma [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B074.