Systemic immune mediators predict therapeutic response and tumor-infiltrating lymphocyte intensity in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer defined by the lack of expression of estrogen receptor, progesterone receptors, and of the human epithelial growth factor receptor 2. Neoadjuvant chemotherapy has proven efficacy in the treatment of TNBC, and a pathological complete response (pCR) is predictive of improved long-term survival. The immune response exerts a vital role in response to neoadjuvant chemotherapy, as indicated by the relation between the percentage of stromal tumor-infiltrating lymphocytes (TILs) in pre-treated tumor tissue samples and the likelihood of achieving pCR. Despite this, the relationship between the systemic immune response and the tumor microenvironment is unclear. In this prospective study, we determined the systemic plasma immune profile of TNBC patients before treatment using a panel of 27 immune mediators and measured the percentage of TILs from the same patients. Patients who demonstrated pCR had significantly higher systemic immune mediators; GM-CSF, FGF-basic, VEGF, IL-2, and IL-5, than the non-responders. Moreover, responders displayed a strong positive correlation between the cytokines IFN-γ and IL-7 with the percentage of TILs, while non-responders had a negative or no correlation. Finally, systemic immune mediator levels before treatment predict pCR (AUC range 0.64 - 0.71), and the combination of immune mediators and TILs improved pCR prediction (AUC 0.71 - 0.82). In conclusion, increased systemic immune mediators reflect increased TILs percentage and act as potential predictive biomarkers of pCR for TNBC patients submitted to neoadjuvant chemotherapy.