Immunological effect of hydrogen gas.

Abstract

e15546 Background: In cancer patients, the affected microenvironment causes metabolic insufficiency of terminal CD8+ T cells, characterized by persistent loss of mitochondrial function and mass, typically following progressive loss of PPAR-gamma co-activator 1 alpha (PGC-1α). Consequently, terminal CD8+T cells become exhausted CD8+ T cells expressing PD-1 molecule. According to recent reports, nivolumab may not be effective for the exhausted CD8+ T cells with mitochondrial dysfunction. Hydrogen gas is reported to activate PGC-1α and enhance mitochondrial function, thereby potentially restoring the exhausted CD8+ T cells and improving the clinical efficiency of nivolumab. Methods: Using flow cytometry, we investigated PD-1 expression in CD8+ T cells in the peripheral blood of 55 patients with stage IV colorectal carcinoma, before and after hydrogen gas treatment. Further, we compared the progression-free survival (PFS) and overall survival (OS), using Cox and Kaplan-Meier survival analyses, between 12 patients treated with nivolumab only, and 14 patients treated with nivolumab + hydrogen gas. Results: Hydrogen gas reduced the number of terminal PD-1+CD8+ T cells in 35 of 55 patients and increased terminal PD-1−CD8+ T cells in 39 of 55 patients. Multivariate analyses demonstrated that the ratio of terminal PD-1+CD8+ T cells before and after treatment with hydrogen gas (terminal PD-1+CD8+ T cell ratio) was an independent predictor of PFS [hazard ratio (HR) 6.459, 95 % confidence interval (CI) 2.384–17.50, p < 0.0001] and OS (HR 2.957, 95 % CI 1.185–7.378, p = 0.020). Additionally, patients with higher terminal PD-1+CD8+ T cell ratio had shorter survival rates than those with lower ratio (log rank test, p < 0.0001 for PFS, p = 0.004 for OS), whereas the high terminal PD-1−CD8+ T cell ratio corresponded to longer survival rates than the lower ratio (log rank test, p = 0.004 for PFS, p = 0.024 for OS). Patients treated with nivolumab + hydrogen gas showed a significantly longer OS than those treated with nivolumab only. Conclusions: These results suggest that hydrogen gas restored terminal PD-1+CD8+ T cells to improve PFS and OS in patients with colorectal carcinomas and to enhance clinical effects in those treated with nivolumab, possibly by activating mitochondrial function.