Baseline T cell dysfunction by single cell network profiling in metastatic breast cancer patients.

ABSTRACT: BACKGROUND:We previously reported the results of a multicentric prospective randomized trial of chemo-refractory metastatic breast cancer patients testing the efficacy of two doses of TGF? blockade during radiotherapy. Despite a lack of objective responses to the combination, patients who received a higher dose of TGF? blocking antibody fresolimumab had a better overall survival when compared to those assigned to lower dose (hazard ratio of 2.73, p?=?0.039). They also demonstrated an improved peripheral blood mononuclear cell (PBMC) counts and increase in the CD8 central memory pool. We performed additional analysis on residual PBMC using single cell network profiling (SCNP). METHODS:The original trial randomized metastatic breast cancer patients to either 1 or 10?mg/kg of fresolimumab, every 3?weeks for 5?cycles, combined with radiotherapy to a metastatic site at week 1 and 7 (22.5?Gy given in 3 doses of 7.5?Gy). Trial immune monitoring results were previously reported. In 15 patients with available residual blood samples, additional functional studies were performed, and compared with data obtained in parallel from seven healthy female donors (HD): SCNP was applied to analyze T cell receptor (TCR) modulated signaling via CD3 and CD28 crosslinking and measurement of evoked phosphorylation of AKT and ERK in CD4 and CD8 T cell subsets defined by PD-1 expression. RESULTS:At baseline, a significantly higher level of expression (p?

SUBMITTER: Formenti SC 

PROVIDER: S-EPMC6624899 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature