YY1 Lactylation Elicits CARD9 Deficiency in Dendritic Cells Promoting Pancreatic Cancer Immune Escape

Area of Science:

• Immunology
• Cancer Biology
• Biochemistry

Background:

• Pancreatic cancer (PC) cells inhibit anti-tumor immunity by suppressing dendritic cell (DC) function.
• Caspase-recruitment domain-containing protein 9 (CARD9) deficiency in DCs exacerbates PC progression, but the mechanism of CARD9 downregulation is unclear.

Purpose of the Study:

• To elucidate the mechanism by which pancreatic cancer cells downregulate CARD9 expression in DCs.
• To identify upstream regulators and molecular events involved in CARD9 suppression.
• To understand the role of this regulatory axis in PC immune escape.

Main Methods:

• Analysis of CARD9 expression in PC tumors and correlation with clinicopathological stages and DC function.
• In vitro experiments assessing the impact of PC cells on DC maturation and CD8+ T cell activation.
• Identification of transcription factors regulating CARD9 promoter activity.
• Investigation of lactate-induced post-translational modifications of identified transcription factors.
• Enzymatic assays to identify lactylation writers and erasers.

Main Results:

• CARD9 expression is downregulated in PC tumors and linked to advanced stages and DC dysfunction.
• PC cells reduce CARD9 expression, impairing DC maturation and CD8+ T cell activation.
• YY1 was identified as a repressor of CARD9, and its activity is modulated by lactylation.
• Tumor-derived lactate induces YY1 lactylation at K183 via p300 (writer) and HDAC2 (eraser), enhancing YY1 stability and CARD9 repression.
• This axis promotes PC immune escape.

Conclusions:

• A novel regulatory axis involving lactate, p300/HDAC2, YY1 lactylation, and CARD9 suppresses DC function in pancreatic cancer.
• This mechanism contributes to immune evasion in PC.
• Targeting this axis may offer therapeutic strategies for pancreatic cancer.