Abstract 726: The retinoid X receptor agonist MSU42011 enhances efficacy of anti-PD1 therapy in a HER2+ breast cancer model through a CD4-IL12 axis
Authors: Leal Ana Sofia , Liby Karen T. 
Published: March 2024

Abstract
Immunotherapy is rarely effective in breast cancer and most current therapeutic options fail to target the stromal compartment. We have developed a new small molecule, MSU42011, that induces tumor regression in experimental models of Kras-driven lung cancer and HER2+ breast cancer. This tumor regression is dependent on a functional immune system. Here, we dissected the tumor stroma, revealing a CD4 and IL12a dependency for the anti-tumor activity of MSU42011. Cancer immunotherapy responses are mostly driven by CD8 T cells. Using a murine HER2+ tumor model, anti-CD8 antibodies (200ug/mouse) were injected 24 hours before treatment with MSU42011 (100MG/KG in power diet) was started. Mice were maintained on diet for 10 days. Anti-CD8 antibodies were also administered on days 3, 7 and 10. The combination did not affect the inhibition of tumor growth by MSU42011, suggesting that its anti-tumor efficacy is not dependent on CD8 T cells. In contrast, tumors treated with MSU42011 and anti-CD4 antibodies grew (p=0.0016 versus MSU42011 alone) at the same rate as tumors treated with control diet (p=0.0139 versus MS42011). Furthermore, anti-CD4 reversed inhibition of tumor growth by MSU42011 in a carcinogen-induced lung tumor model. Interestingly, MSU42011 increased the levels of IL12 by 4x (p=0.01) and IFN by 8x (p=0.03) compared to the controls. These data suggest that MSU42011 increased Th1 CD4 T cell polarization; the increase in IL12 was lost following CD4 T cell depletion. Following depletion of IL12a with antibodies (loading dose of 1 mg, followed by 0.5mg per mouse IP), tumors treated with the combination of MSU42011 and anti-IL12a antibodies grew at the same rate as the controls. T cell engagement with MSU42011 suggests that this small molecule is a good candidate for combination with immunotherapy. HER2+ MMTV-Neu mice with established tumors were treated with the combination of MSU42011 and anti-PD1 antibodies. Treatment with MSU42011 at 100mg/Kg of diet for 10 days, followed by anti-PD1 antibodies (200ug) twice weekly failed to increase survival. In contrast, 2 doses of anti-PD1 antibodies (300ug), followed by treatment with MSU42011 increased survival by 10 days compared to controls. The tumors in the MSU42011+anti-PD1 group initially grew rapidly, with increased redness and heat, suggesting an enhanced inflammatory response. When anti-PD1 antibodies were given at a lower loading dose (200ug and then 100ug twice weekly) followed by a higher dose of MSU42011 (300 mg/Kg of diet), survival markedly increased (p=0.052). These findings demonstrate that activation of RXR in the stroma can be used to increase the effectiveness of immunotherapy.
Citation Format: Ana Sofia Leal, Karen T. Liby. The retinoid X receptor agonist MSU42011 enhances efficacy of anti-PD1 therapy in a HER2+ breast cancer model through a CD4-IL12 axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 726.