IL-6 Signaling in Peripheral Blood T Cells Predicts Clinical Outcome in Breast Cancer
Lei Wang1, Andrea K. Miyahira1, Diana L. Simons1, Xuyang Lu2, Andrew Y. Chang7, Carrie Wang1, Maria A. Suni3, Vernon C. Maino3, Frederick M. Dirbas4, John Yim6, James Waisman5, and Peter P. Lee1*
1Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
2Department of Biostatistics, UCLA, CA 90095, USA
3BD Biosciences, San Jose, CA 95131, USA
4Department of Surgery, Stanford University, Stanford, CA 94305, USA
5Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
6Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
7Department of Medicine, Stanford University Medical Center, Stanford, CA 94305, USA
Inflammation and adaptive immune responses play opposing roles in regulating tumor development, progression, and metastasis. Interleukin-6 (IL-6) is a pleiotropic cytokine with both pro- and anti-inflammatory properties which acts directly on cancer cells to promote their survival and proliferation. Elevated serum IL-6 levels negatively correlate with survival of cancer patients, which is generally attributed to the direct effects of IL-6 on cancer cells. How IL-6 modulates the host immune response in cancer patients is unclear. Here we show the IL-6 signaling response in peripheral blood T cells is impaired in breast cancer (BC) patients and is associated with blunted Th17 differentiation. The mechanism identified involved downregulation of gp130 and IL-6Rα in BC patients and was independent of plasma IL-6 levels. Importantly, defective IL-6 signaling in peripheral blood T cells at diagnosis correlated with worse relapse-free survival (RFS). These results indicate that intact IL-6 signaling in T cells is important for controlling cancer progression. Furthermore, they highlight a potential for IL-6 signaling response in peripheral blood T cells at diagnosis as a predictive biomarker for clinical outcome of BC patients.
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