Alternate Cooling and Heating Thermal Physical Treatment: An Effective Strategy Against MDSCs in 4T1 Mouse Mammary Carcinoma

Abstract

An alternate thermal physical treatment was developed to destroy tumor tissue using liquid nitrogen cooling and RF heating treatment in our pervious study. Our pervious reports had shown that anti-tumor immunity was induced by the alternate treatment. Myeloid derived suppressor cells (MDSCs) are a subset of heterogeneous, bone marrow derived hematopoietic cells that accumulate in the spleen, bone marrow, blood and tumor sites of tumor-bearing mice and cancer patients. MDSCs are one of the key suppressor cells that regulate anti-tumor immune responses in tumor-bearing hosts. MDSCs have been shown to inhibit the function of various types of cells mediating anti-tumor immunity, such as T cells, B cells, NK cells and dendritic cells. MDSCs are recruited specifically to the tumors and contribute indirectly to angiogenesis, growth and metastasis. MDSCs also exert resistance to cancer therapies, such as anti-VEGF strategies and cancer immunotherapy. Given the role of MDSCs in tumor invasion and metastasis and anti-tumor immune responses, therapeutics targeting MDSCs might offer a new strategy for cancer treatment. In this study, the therapeutic effect and MDSCs changes after the alternate cooling and heating treatment was studied using the 4T1 murine mammary carcinoma, a common animal model of human metastatic breast cancer. Due to its highly invasive and poorly immunogenic characters, the 4T1 tumor could cause death even after the primary tumor was surgically removed. The treatment was carried out when micro-metastases were well established. Comparisons were made with the results from the surgery and hyperthermia groups, respectively. The results showed that MDSCs in blood increased rapidly with time after tumor inoculation, and in 66 days, all the mice died in the control group. The statistical results indicated a significant increase in circulating MDSC numbers at different tumor growth stages. In the surgical resection group, MDSCs in blood did not decrease, but increased rapidly to a level much higher that of the control group in 39 day after tumor inoculation. In the hyperthermia group, MDSCs in blood increased rapidly with time after tumor inoculation, and in 39 day, MDSCs was up to 3 times higher than that of the control group. Mice died in 45 day after initial tumor inoculation. But in the alternate treatment group, the number of MDSCs decreased rapidly and recovered to the normal healthy level in 11 days after the treatment. No metastatic tumor could be observed in these mice, and they were in good physiological conditions as observed in the following 3 month. In conclusion, the alternate treatment was found extremely effective against MDSCs in the very aggressive and highly metastatic mouse mammary carcinoma. The good prognosis was expected in relation to the significant decrease in MDSCs and thus the relief of the immune suppression, induced by the alternate cooling and heating treatment. It could be further developed as a novel therapeutic method against metastatic tumor. On the other hand, combining the alternate treatment with other strategies, such as anti-VEGF and cancer immunotherapy, the best therapeutic effect would be achieved through synergy.