Hydrogen gas restores exhausted CD8+ T�cells in patients with advanced colorectal cancer to improve prognosis

Abstract

Exhausted cluster of differentiation (CD)8 + T cells lose immunological activity due to mitochondrial dysfunction caused by peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) inactivation, resulting in a poor prognosis in patients with cancer. As hydrogen gas was recently reported to activate PGC-1α, the present study investigated whether it restores exhausted CD8 + T cells to improve prognosis in patients with stage IV colorectal cancer. A total of 55 patients with histologically and clinically diagnosed stage IV colorectal carcinoma were enrolled between July 2014 and July 2017. The patients inhaled hydrogen gas for 3 h/day at their own homes and received chemotherapy at the Tamana Regional Health Medical Center (Tamana, Kumamoto, Japan). The CD8 + T cells were isolated from the peripheral blood and their phenotype was analyzed by flow cytometry. It was found that exhausted terminal programmed cell death 1 (PD-1) + CD8 + T cells in the peripheral blood are independently associated with worse progression-free survival (PFS) and overall survival (OS). Notably, hydrogen gas decreased the abundance of exhausted terminal PD-1 + CD8 + T cells, increased that of active terminal PD-1 -CD8 + T cells, and improved PFS and OS times, suggesting that the balance between terminal PD1 + and PD1 -CD8 + T cells is critical for cancer prognosis. Therefore, a novel system for patient classification (category 1-4) was developed in the present study based on these two indices to assist in predicting the prognosis and therapeutic response.Collectively, the present results suggested that hydrogen gas reverses imbalances toward PD-1 + CD8 + T cells to provide an improved prognosis.

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

“…As hydrogen gas is reported to activate PGC1-α (14), it is also one of the mitochondrial activation mediators. Recently, we reported that hydrogen gas could restore exhausted CD8 + T cells to active CD8 + T cells via mitochondrial activation (7). This implies that hydrogen gas may improve the clinical effects of nivolumab, as reported by Chamoto et al (6).…”

“…Honjo et al, reported that mitochondrial activation chemicals such as Bezafibrate, an activator of PGC1-α, synergize with nivolumab for T cell-dependent antitumor activity (6), suggesting that T cells with severe metabolic insufficiency equivalent to exhausted T cells are highly involved in low clinical outcomes of nivolumab and reinvigoration of exhausted T cells is incompletely achieved by checkpoint blockade such as nivolumab only, and consequently, metabolic reprogramming must be preceded for enhancement of checkpoint blockade (5). Recently, we reported that the proportion of PD-1 + terminal CD8 + T cells containing PDT+ and PDT-(exhausted CD8 + T cells) in the peripheral blood of colorectal cancer patients was reduced by hydrogen gas, an activator of PGC1-α, leading to better prognosis (7). Furthermore, enforced expression of PGC1α in exhausted T cells results in superior antitumor T cell function (5,8).…”

Hydrogen: A Novel Option in Human Disease Treatment

“…Other authors reported that H 2 inhalation reduced the size of the endometrial explants, inhibited cell proliferation, improved SOD, and regulated the expression of matrix metalloproteinase 9 and cyclooxygenase 2 in an endometriosis rat model [ 130 ]. HRS is effective in attenuating ovary injury induced by I/R [ 131 ] and cisplatin [ 132 ]. HW improved serum anti-Müllerian hormone levels and reduced ovarian granulosa cell apoptosis in a mouse immune premature ovarian failure model induced by zona pellucida glycoprotein 3 [ 133 ].…”

Progress in the Use of Molecular Hydrogen for Cancer Treatment

“…Loss of immunological activity of differentiation cluster CD8 + T cells is associated with the inactivation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), which causes mitochondrial dysfunction, and is widely found in patients with advanced cancer [22]. In 2018, Akagi J et al found that hydrogen gas could activate PGC-1α and restore the exhausted CD8 + T cells in stage IV colorectal carcinoma patients, suggesting that hydrogen could improve the prognosis of patients with advanced cancer [22].…”