Hydrogen Sulfide Creates a Favorable Immune Microenvironment for Colon Cancer

Area of Science:

• Oncology
• Immunology
• Biochemistry

Background:

• Immunotherapy shows promise for colorectal cancer but benefits only a subset of patients.
• Hydrogen sulfide (H2S) is implicated in colorectal cancer development and immune evasion.
• Mechanisms linking H2S to colorectal cancer immune escape require further elucidation.

Purpose of the Study:

• To investigate the role of H2S in the colorectal cancer immune microenvironment.
• To identify molecular targets for reversing H2S-mediated tumor-promoting functions.
• To explore strategies for enhancing immunotherapy efficacy in colorectal cancer.

Main Methods:

• Analysis of H2S levels in colorectal cancer tissues.
• Modulation of H2S levels using genetic (CBS+/- mice) and dietary (sulfur amino acid-restricted diet - SARD) approaches.
• Flow cytometry to assess CD8+ T-cell and Treg populations.
• Evaluation of anti-PD-L1 and anti-CTLA-4 immunotherapy efficacy.
• Biochemical assays to determine H2S-mediated protein persulfidation (ENO1 and ELK4).

Main Results:

• Colorectal cancer tissues exhibited significantly elevated H2S levels.
• Decreased H2S levels led to a reduced CD4+CD25+Foxp3+ Treg population and an increased CD8+ T-cell/Treg ratio.
• H2S depletion enhanced the therapeutic efficacy of anti-PD-L1 and anti-CTLA-4 treatments.
• H2S promotes Treg activation via ENO1 persulfidation and inhibits CD8+ T-cell migration via ELK4 persulfidation.

Conclusions:

• Reducing H2S levels creates an anti-tumor immune microenvironment in colorectal cancer.
• H2S depletion reverses tumor-supportive functions by modulating Treg activation and CD8+ T-cell migration.
• A sulfur amino acid-restricted diet (SARD) is a potential dietary strategy to improve immunotherapy response in colorectal cancer.