The thyroid status modulates the composition of tumor microenvironment and the antitumor immune response in a 4t1 murine breast cancer model

Abstract

Several findings suggest that the patient?s hormonal context plays a crucial role in determining the outcome of cancer. However, very little is known about the nature of thyroid hormone action on tumor growth. Our aim was to evaluate the effect of thyroid status on the immunity and microenvironment of breast cancer. For this, Balb/c mice were orthotopically inoculated with 4T1 breast carcinoma cells after the treatment with thyroxine (12mg/l) for 30 days or propylthiouracil (500mg/l) for 15 days in the drinking water to obtain hyperthyroid (hyper) or hypothyroid (hypo) mice, respectively. An increased tumor growth rate was seen in hyper mice compared to controls (p<0.05), while hypo mice bared tumors with reduced volume (p<0.05), but developed a greater number of lung metastases (p<0.05). The analysis of immune subsets indicated that hyper tumors presented a decreased immune cell infiltration (p<0.05), with a reduced percentage of activated CD4+ and CD8+ T cells (p<0.05). Tumor draining lymph nodes (TDLN) of hyper mice also showed a reduced number of activated CD8+ T cells (p<0.01) and NK cells (p<0.01), but increased percentage of activated CD4+ T cells (p<0.001). Additionally, a decreased number (p<0.01) and activity (p<0.05) of NK cells was detected in hyper spleens, accompanied by increased percentages of MDSC (p<0.05). On the other hand, hypo mice showed a higher percentage of activated CD8+ tumor infiltrating T cells (p<0.05), but a decreased number of these cells in TDLN (p<0.05). To evaluate the effect of thyroid status on the migration of mesenchymal stromal cells (MSCs) to 4T1 tumors, MSC were inoculated in the tail vein of tumor-bearing mice and analyzed by in vivo imaging. Hyper tumors and lungs showed a decreased presence of MSC compared to control and hypo mice (p<0.05). Our results suggest that the thyroid status modulates the antitumor immune responses and the migration of MSC to the 4T1 tumors, thus modifying tumor growth and metastasis formation.