激活RXR核受体可改善小鼠乳腺癌免疫治疗的生存期和治疗窗

The retinoid X receptor (RXR) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors. Bexarotene, the only approved RXR agonist, is used in refractory cutaneous T cell lymphoma but lacks effect on solid tumors. Based on structure-activity-relationships (SAR) we selected MSU42011, as a more potent and specific RXR agonist.Treatment with the RXR agonist MSU42011 (300 mg/Kg diet) reduced tumor burden and increased survival in a MMTV-Neu murine model of HER2+ breast cancer (p=0.01, 55 days vs 62 days median survival, respectively). HER2 breast cancer patients have not benefited from the approval of immunotherapy. However, HER2 positive stomach cancer patients see benefit when treated with anti-PD1, which is now approved for clinical use. We previously shown that MSU42011 can be combined with immunotherapy in a lung cancer murine model, therefore we tested the combination of MSU42011 with anti-PD1 in MMTV-Neu mice. The combination of MSU42011+anti-PD1 significantly (median survival 69 days) increases survival when compared with mice that receive either only control (p=0.008) or anti-PD1 (p= 0.05, median survival 53 days). No obvious side effects were observed in either anti-PD1 alone or in combination with MSU42011 groups. MMTV-Neu mice were treated as above and euthanized at 40 days after treatment initiation for tumor immunophenotyping. Mice receiving MSU42011 or MSU42011+anti-PD1 showed a significant reduction in the expression of CD206 and PDL-1, two immunosuppressive molecules, in inflammatory (p=0.03) and resident (p=0.05, p=0.005) monocytes. CD11c (p=0.04) and CD11b (p=0.03) tumor associated macrophages (TAMs) had a significant reduction in PDL-1 expression in both MSU42011 and MSU42011+anti-PD1 groups. The reduction in the immunosuppressive CD206 and PDL-1 expression in the myeloid lineage, was associated with a significant increase in the infiltration of CD8 T cells (p=0.01), as well as in the activation markers of CD8 T cells (CD44, p=0.05; CD69, p=0.007).In the highly aggressive MMTV-PyMT murine model of triple negative breast cancer (TNBC), MSU42011 treatment significantly (p= 0.001) prolonged survival (median 39 vs 49 days). Flow cytometry of tumors at 28 days of treatment showed a decreased number of TAMs (36.6% vs 20.2%) and an increased number of CD8 T cells (3.4% vs 5.9%). Moreover at this time point only 1 of 10 mice had visible lung metastasis in the MSU42011 group compared with control where 4 of 10 mice had lung metastasis, additionally, one mouse that had a bone metastasis. In conclusion, MSU42011 increased recruitment and activation of CD8 T cells and a decrease of tumor promoting myeloid cells in both HER2+ and TNBC murine mammary tumors. These data, in combination with our previous work shows that the RXR agonist MSU42011 reduces tumor growth by modulating the tumor microenvironment and can safely be combined with anti-PD1.