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Abstract Bone metastases are a highly debilitating complication in more than 70% of patients with advanced breast and prostate cancer. Currently approved treatments fail to cure bone metastases or increase patient survival. Although immunotherapies can cause a durable response in some patients, it seems that their efficacy is limited in bone metastases, which could be due to a cold metastatic microenvironment. Our aim was to identify immunosuppressive factors in bone metastases and target them using a drug-repositioning type approach. We used a syngeneic model in which 4T1 triple-negative breast cancer cells derived from a Balb/C mouse are inoculated in the left cardiac ventricle of Balb/C mice to cause osteolytic bone metastases. Using flow cytometry, we found that the bone marrow of mice with 4T1 bone metastases is enriched in large cells with a high SSC index that could be myeloid-derived suppressor cells. We confirmed that the inoculation of 4T1 cells increased the amount of CD11b+ Ly6G+ Ly6Clo ROShi and CD11b+ Ly6G- Ly6Chi NOhi cells. Both cell types were isolated from bone metastases and prevented the proliferation of CD8+ T cells ex vivo, confirming they were polymorphonuclear- (PMN-) and monocytic-MDSCs (M-MDSCs), respectively. In addition, both types could differentiate into osteoclasts that cause bone loss. Reviewing the current literature, we found that FDA-approved sildenafil (a PDE-5 inhibitor), zoledronic acid (a bone resorption inhibitor), and 5-fluorouracil (5-FU, a chemotherapeutic agent) can decrease MDSCs in other cancer models. However, sildenafil (20mg/kg, i. p. , every 2 days) and zoledronic acid (25µg/kg, s. c. , 3x/week) did not decrease the amount of MDSCs in 4T1 bone metastases. 5-FU (i. p. , 4 inoculations) at 50mg/kg prevented the 4T1-induced splenomegaly and the increase of PMN- and M-MDSCs but seemed to decrease the number of T cells in bone metastases. Thus, we tested the efficacy of a lower number of inoculations. A single inoculation of 5-FU was not efficient, while 2 or 3 inoculations of 5-FU (50mg/kg) prevented the splenomegaly and the histological damage due to extramedullary hematopoiesis in the spleen. In 4T1 bone metastases, there was a decrease of PMN-MDSCs and an increase of the number of CD4+ and CD8+ T cells. On radiographs, 2 or 3 inoculations of 5-FU (50mg/kg) significantly decreased the area of the osteolytic lesions caused by 4T1 cells (-57% and -60%, respectively, compared to placebo, P0. 005). In conclusion, our results show that functional PMN- and M-MDSCs can increase and accumulate in the microenvironment of breast cancer bone metastases and that an optimized treatment with 5-FU can prevent this expansion of MDSC, increasing T cell infiltration in bone metastases and decrease the associated bone lesions. Treatment with 5-FU could then contribute to turning bone metastases from a cold to a hot microenvironment and increase the efficacy of immunotherapies in patients. Citation Format: Pierrick G. J. Fournier, Paloma Almeida Luna, Danna Arellano, Samanta Jiménez, Felipe Olvera, Patricia Juárez. 5-Fluorouracil decreases MDSC and the development of osteolytic bone metastases from breast cancer in mice 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 (6Suppl): Abstract nr 5281.
Fournier et al. (Fri,) studied this question.