Hydrogen gas activates coenzyme Q10 to restore exhausted CD8+ T cells, especially PD‑1+Tim3+terminal CD8+ T cells, leading to better nivolumab outcomes in patients with lung cancer
Affiliations: Department of Surgery, Tamana Regional Health Medical Center, Kumamoto 865‑0005, Japan, Department of Gastroenterological Surgery Kumamoto University, Kumamoto 860‑8556, Japan
- Published online on: September 18, 2020 https://doi.org/10.3892/ol.2020.12121
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As previously reported, hydrogen gas improves the prognosis of patients with cancer by restoring exhausted CD8+ T cells into active CD8+ T cells, possibly by activating mitochondria. As mitochondrial activators exhibit synergistic effects with nivolumab, the current study investigated whether hydrogen gas also affects the clinical outcomes of nivolumab. A total of 42 of 56 patients with lung cancer treated with nivolumab received hydrogen gas. Exhausted markers (PD‑1 and Tim‑3) on cell populations in the CD8+ T cell differentiation pathway were analyzed using flow cytometry. The concentration of coenzyme Q10 (CoQ10) was measured as a marker of mitochondrial function. The 42 patients treated with hydrogen gas and nivolumab (HGN) indicated a significantly longer overall survival (OS) compared with those treated with nivolumab only (n=14). In multivariate analysis, PD‑1+Tim‑3+terminal CD8+ T cells (PDT+) were an independent poor prognostic factor in OS, and CoQ10 showed a tendency to be associated with improved OS. The change in the rate of PDT+ and CoQ10 after vs. before HGN (PDT+ ratio and CoQ10 ratio, respectively) revealed that patients with low PDT+ ratio (<0.81) and high CoQ10 ratio (>1.175) had significantly longer OS compared with those with high PDT+ ratio and low CoQ10 ratio. Furthermore, PDT+, with a significant reverse correlation with CoQ10, was significantly lower in patients with high CoQ10 and/or CoQ10 ratio than in those low CoQ10 and/or CoQ10. Hydrogen gas has been suggested to enhance the clinical efficacy of nivolumab by increasing CoQ10 (mitochondria) to reduce PDT+, with PDT+ and CoQ10 as reliable negative and positive biomarkers of nivolumab, respectively.