New mechanistic insights into the role of inflammatory molecules in cancer progression
Immune checkpoint inhibitors have revolutionized cancer treatment, yet many colorectal tumors remain resistant. Even among patients who initially respond, more than half eventually develop resistance, highlighting the need to better understand how tumors evade immune attack.
This research, published in Nature Communications, sheds new light on how inflammatory cytokine IL-26 contributes to colorectal cancer progression and immune checkpoint inhibitor resistance. Assistant Professor Takumi Itoh and his team from Juntendo University demonstrated that IL-26 produced by CD8⁺ type 17 T cells enters tumor cells, directly impacting their epigenome.
By interacting with STAT1 and recruiting transcription regulators like BRD4, IL-26 initiates an epigenetic program that increases the expression of CXCL chemokines (by thousands of times), attracting neutrophils. These neutrophils weaken antitumor CD8⁺ T-cell activity, enabling immune evasion and reducing the effectiveness of anti-PD-1 immunotherapy.
The study reveals that targeting IL-26, BRD4, CXCL receptors, or neutrophils restores antitumor immunity and enhances immunotherapy responses in preclinical models. The findings identify a novel mechanism linking inflammation, epigenetic remodeling, and immunotherapy resistance, presenting a promising therapeutic target to improve colorectal cancer treatment.
Itoh emphasized the potential of developing therapeutic strategies targeting IL-26 or disrupting its epigenetic program to complement existing anti-PD-1 therapies, potentially overcoming treatment resistance in a variety of cancers and inflammatory diseases.
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