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

Oncol Rep. 2019 Jan;41(1):301-311. doi: 10.3892/or.2018.6841. Epub 2018 Nov 1.


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.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Capecitabine
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / therapy*
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / therapeutic use
  • Female
  • Fluorouracil / analogs & derivatives
  • Fluorouracil / therapeutic use
  • Humans
  • Hydrogen / therapeutic use*
  • Japan
  • Lymphocyte Activation / immunology
  • Male
  • Masks
  • Middle Aged
  • Neoplasm Staging
  • Oxaloacetates
  • Prognosis
  • Programmed Cell Death 1 Receptor / immunology
  • Programmed Cell Death 1 Receptor / metabolism*
  • Progression-Free Survival
  • Respiratory Therapy / adverse effects
  • Respiratory Therapy / instrumentation
  • Respiratory Therapy / methods*
  • Treatment Outcome


  • Oxaloacetates
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Deoxycytidine
  • Capecitabine
  • Hydrogen
  • Fluorouracil

Supplementary concepts