Shawn J Rice1, Xin Liu1, Jianhong Zhang1, Bei Jia1, Hong Zheng2, Chandra P Belani3. 1. Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA 17033, USA. 2. Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA 17033, USA; Department of Medicine, Penn State College of Medicine, Hershey, PA 17033, USA. 3. Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA 17033, USA; Department of Medicine, Penn State College of Medicine, Hershey, PA 17033, USA. Electronic address: cbelani@psu.edu.
Abstract
OBJECTIVES: High levels of circulating interleukin-6 (IL-6) are associated with a poor prognosis in many types of cancer including non-small cell lung cancer (NSCLC). While the inflammatory cytokine can stimulate the immune system and promote tumor growth, it remains unclear how circulating IL-6 can potentiate a poor prognosis. We hypothesized that a mechanism for IL-6-associated poor prognosis is that these patients would have altered T-cell populations and impaired T-cell signaling. MATERIALS AND METHODS: Plasma levels of IL-6 were measured using a Cytometric Bead Array. T-cell populations from Non-small cell lung cancer patients were characterized using surface markers by flow cytometry, and signaling in the T-cell populations were measured by PhosFlow cytometry. RESULTS: We determine that patients with high circulating IL-6 levels had distinct T cell characteristics relative to those with low levels. Patients with high levels of IL-6 had significantly more Treg cells and elevated Programmed cell death protein-1 (PD-1) expression on CD4+, CD8+, Treg, and Th17 cells. These patients also showed impaired signal transducer and activator of transcription-1 (STAT1) signaling upon stimulation with IL-6 and phorbol 12-myristate 13-acetate (PMA), and T-Cells from a healthy donor that were treated for four days with IL-6 displayed a similar muting of STAT signaling, which verified the effect seen in patient samples. CONCLUSIONS: This work directly links circulating IL-6 with other poor prognostic indicators, STAT1 and PD-1, and highlights the effects of circulating IL-6 on the immune system. Our data suggest that alteration in T cell populations and function may be a mechanism underlying the poor prognosis seen in NSCLC patients with high IL-6 levels.
OBJECTIVES: High levels of circulating interleukin-6 (IL-6) are associated with a poor prognosis in many types of cancer including non-small cell lung cancer (NSCLC). While the inflammatory cytokine can stimulate the immune system and promote tumor growth, it remains unclear how circulating IL-6 can potentiate a poor prognosis. We hypothesized that a mechanism for IL-6-associated poor prognosis is that these patients would have altered T-cell populations and impaired T-cell signaling. MATERIALS AND METHODS: Plasma levels of IL-6 were measured using a Cytometric Bead Array. T-cell populations from Non-small cell lung cancerpatients were characterized using surface markers by flow cytometry, and signaling in the T-cell populations were measured by PhosFlow cytometry. RESULTS: We determine that patients with high circulating IL-6 levels had distinct T cell characteristics relative to those with low levels. Patients with high levels of IL-6 had significantly more Treg cells and elevated Programmed cell death protein-1 (PD-1) expression on CD4+, CD8+, Treg, and Th17 cells. These patients also showed impaired signal transducer and activator of transcription-1 (STAT1) signaling upon stimulation with IL-6 and phorbol 12-myristate 13-acetate (PMA), and T-Cells from a healthy donor that were treated for four days with IL-6 displayed a similar muting of STAT signaling, which verified the effect seen in patient samples. CONCLUSIONS: This work directly links circulating IL-6 with other poor prognostic indicators, STAT1 and PD-1, and highlights the effects of circulating IL-6 on the immune system. Our data suggest that alteration in T cell populations and function may be a mechanism underlying the poor prognosis seen in NSCLCpatients with high IL-6 levels.
Authors: Alexander Roberts; Lindsay Bentley; Tina Tang; Fay Stewart; Chiara Pallini; Joel Juvvanapudi; Graham R Wallace; Alison J Cooper; Aaron Scott; David Thickett; Sebastian T Lugg; Hollie Bancroft; Bridget Hemming; Charlotte Ferris; Gerald Langman; Andrew Robinson; Joanne Chapman; Babu Naidu; Thomas Pinkney; Graham S Taylor; Kristian Brock; Zania Stamataki; Catherine A Brady; S John Curnow; John Gordon; Omar Qureshi; Nicholas M Barnes Journal: Sci Rep Date: 2021-02-17 Impact factor: 4.379