The Effect of Intratumoral Interrelation among FOXP3+ Regulatory T Cells on Treatment Response and Survival in Triple-Negative Breast Cancer

SIMPLE SUMMARY: Triple-negative breast cancer (TNBC) is a disease in which immunotherapy is more successful than in other subtypes of breast cancer. We describe a specific immune response involved in the infiltration of regulatory T cells in TNBC. Focusing on interleukin 33 (IL-33) and transforming growth factor beta 2 (TGFb2), which were identified by network analysis, we examined the therapeutic effect and prognosis of patients by immunohistostaining for these markers. We found that FOXP3 is a good prognostic factor for patients with high IL-33 and TGFb2 in the tumor. This finding may lead to the development of novel therapeutic strategies such as inducing these cytokines. It also provides deeper insight into the role of FOXP3, a universal marker of regulatory T cells, in TNBC. ABSTRACT: Triple-negative breast cancer (TNBC) is characterized by an active immune response. We evaluated intratumoral interrelation between FOXP3+ tumor-infiltrating lymphocytes and other cytokines in TNBC. Network analysis refined cytokines significantly correlate with FOPX3 in TNBC. Information on the treatment response and prognosis of patients, and survival data from the TGCA and METABRIC databases were analyzed according to refined cytokines. Interleukin (IL)-33 was significantly expressed by TNBC cell lines compared to luminal cell lines (log(2) fold change: 5.31, p < 0.001) and IL-33 and TGFB2 showed a strong correlation with FOXP3 in the TNBC cell line. Immunohistochemistry demonstrated that the IL-33 high group was a significant predictor of complete response of neoadjuvant chemotherapy (odds ratio (OR) 4.12, p < 0.05) and favorable survival compared to the IL-33 low group (OR 6.48, p < 0.05) in TNBC. Survival data from TGCA and METABRIC revealed that FOXP3 was a significantly favorable marker in the IL-33 high group compared to the low IL-33 low group (hazard ratio (HR) 2.1, p = 0.02), and the IL-33 high/TGFB2 high subgroup showed significant favorable prognosis in the FOXP3 high group compared to the FOPX3 low group in TNBC (HR 3.5, p = 0.01). IL-33 and TGFB2 were key cytokines of intratumoral interrelation among FOXP3 in TNBC.