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Synergistic immunochemotherapy exerts efficiently anti-hepatocellular carcinoma effect to induce SAMD4B-APOA2 axis for inhibition of tumor immune evasion

ABSTRACT: The purpose of this study is to speculate TCC (Thalidomide+carmofur+ Cantharidin), may be a promising treatment strategy for patients with advanced HCC.However, there is few research on this novel clinical combination therapy, especially the mechanism of its anti-hepatocellular effect. Therefore, it is necessary to further explore the specific mechanism of triple drug combination in HCC treatment.Here, we prospectively collected the clinical data of 92 patients with unresectable HCC, observed the effective efficacy of TCC in clinical practice, and confirmed in 6 PDX models in mice.Later on, we collected the resected tumors conducted single cell sequencing (scRNA-seq). We found that SAMD4B, especially its expression level, could affect the immune microenvironment. In order to understand the details of its immune regulation mechanism, such as which immune cells PD1 (i.e. PD-L1 receptor regulated by SAMD4B) comes from, we selected 4 patients from low- and high-SAMD4B groups for scRNA-seq.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE222791 | GEO | 2024/01/08

REPOSITORIES: GEO

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Project description:Background: IL-33, a cytokine with pleiotropic functions, is elevated in serum of patients with hepatocellular carcinoma (HCC). This study investigated effects of local IL-33 expression in resected HCC on patient survival and on immunological and molecular tumor microenvironment. Methods: Tissue of resected HCCs was stained for H&E, masson trichrome, alpha smooth muscle actin, IL-33, CD8 and IL-13 and analysed by flow cytometry. Besides histomorphologic evaluation, the immunohistochemical stainings were analysed for the respective cell numbers separately for tumor area, infiltrative margin and distant liver stroma. These findings were correlated with clinical data and patient outcome. Further, gene expression of different HCC risk groups was compared using Micro Arrays. Results: In multivariable analysis, infiltration of HCCs by IL-33+ cells (P=0.032) and CD8+ cells (P=0.014) both independently were associated with prolonged patient survival. Flow cytometry demonstrated that cytotoxically active CD8+CD62L-KLRG1+CD107a+ effectory-memory cells are the main producers of IL-33 in these HCC patients. Using infiltration by IL-33+ and CD8+ cells as two separate factors, a HCC immune score (HCCIS) was designed and evaluated that stratified patient survival (P=0.0004). This HCCIS identified high and low risk patients who differ in gene expression profiles (P<0.001). Conclusion: Infiltration of HCCs by IL-33+ and CD8+ cells is independently associated with prolonged patient survival. We suggest that this is due to an induction of highly effective cytotoxically active CD8+CD62L-KLRG1+CD107a+ effector-memory cells producing IL-33. Based on these two independent factors we established a HCC immune score that provides risk stratification for HCC patients and can be used in the clinical setting. To investigate if HCCIS 0 high risk and HCCIS 2 low risk tumors exhibit a distinct molecular environment and gene expression pattern, RNA from fresh tumor tissue was isolated and analyzed by whole genome Microarray 4 patients with low risk tumors (HCCIS 2) were compared to 4 patients with high risk tumors (HCCIS 0).

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Synergistic immunochemotherapy exerts efficiently anti-hepatocellular carcinoma effect to induce SAMD4B-APOA2 axis for inhibition of tumor immune evasion

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