Effects of 3-HAA on HCC by Regulating the Heterogeneous Macrophages-A scRNA-Seq Analysis

Kynurenine derivative 3-hydroxyanthranilic acid (3-HAA) is known to regulate the immune system and exhibit anti-inflammatory activity by inhibiting T-cell cytokine secretion and influencing macrophage activity. However, the definite role of 3-HAA in the immunomodulation of hepatocellular carcinoma (HCC) is largely unexplored. An orthotopic HCC model and treated with 3-HAA by intraperitoneal injection is developed. Furthermore, cytometry by time-of-flight (CyTOF) and single-cell RNA sequencing (scRNA-seq) analyses are carried out to define the immune landscape of HCC. It is found that 3-HAA treatment can significantly suppress tumor growth in the HCC model and alter the level of various cytokines in plasma. CyTOF data shows that 3-HAA significantly increases the percentage of F4/80(hi)CX3CR1(lo)Ki67(lo)MHCII(hi) macrophages and decreases the percentage of F4/80(lo)CD64(+)PD-L1(lo) macrophages. scRNA-seq analyses demonstrate that 3-HAA treatment is proved to regulate the function of M1 macrophages, M2 macrophages, and proliferating macrophages. Notably, 3-HAA inhibits the proinflammatory factors TNF and IL-6 in multiple cell subsets, including resident macrophages, proliferating macrophages, and pDCs. This study reveals the landscape of immune cell subsets in HCC in response to 3-HAA, indicating that 3-HAA may be a promising therapeutic target for HCC.

Automated summary

It is discovered that 3-hydroxyanthranilic acid (3-HAA) can exhibit anti-inflammatory activity and regulate the immune system by inhibiting T-cell cytokine secretion and influencing macrophage activity. However, its role in the immunomodulation of hepatocellular carcinoma (HCC) has not been well explored. This study develops an HCC model treated with 3-HAA and utilizes CyTOF and scRNA-seq analyses to define the immune landscape of HCC. The findings show that 3-HAA treatment can suppress tumor growth in the HCC model and alter the cytokine levels in plasma, indicating its potential as a therapeutic target for HCC.