Zhen Limin, Zhu Yi, Wu Zhen, Liao Jinyao, Deng Liaoyuan, Ma Qianqian, Wu Qili, Ning Gang, Lin Qiuxiong, Zhou Liya, Huang Yanjie, Zhuo Zewei, Chen Ren, Yu Dongnan
Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China.
Department of Infectious Diseases, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China.
Heliyon. 2024 Feb 28;10(5):e26989. doi: 10.1016/j.heliyon.2024.e26989. eCollection 2024 Mar 15.
Activation of the Hedgehog signaling pathway is linked to the initiation and development of human hepatocellular carcinoma (HCC). However, its impact on clinical outcomes and the HCC microenvironment remains unclear.
We performed comprehensive analyses of Hedgehog pathway genes in a large cohort of HCC patients. Specifically, we utilized univariate Cox regression analysis to identify Hedgehog genes linked to overall survival, and the LASSO algorithm was used to construct a Hedgehog-related gene pattern. We subsequently examined the correlation between the Hedgehog pattern and the HCC microenvironment employing the CIBERSORT and ssGSEA algorithms. Furthermore, Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and the anti-PD-L1 treatment dataset (IMvigor210) are used to evaluate the clinical response of the Hedgehog pattern in predicting immune checkpoint inhibitors.
We found that the Hedgehog activation score (HHAS), a prognostic score based on 11 Hedgehog genes, was significantly associated with HCC patient survival. Patients exhibiting high HHAS experienced markedly reduced survival rates compared to those with low HHAS, and HHAS emerged as an independent prognostic factor for HCC. Functional enrichment analysis unveiled the association of the HHAS phenotype with functions related to the immune system, and further investigation demonstrated that HCC patients exhibiting low HHAS displayed elevated levels of anti-tumor immune activation in CD8 T cells, while high HHAS were linked to immune escape phenotypes and increased infiltration of immune suppressive cells. In addition, in the Immune Checkpoint Inhibitor (ICI) cohort of IMvigor210, patients with higher HHAS had worse ICI treatment outcomes and shortened survival time, indicating that the HHAS is a useful indicator for predicting patient response to immunotherapy.
In summary, our study offers valuable insights for advancing research on Hedgehog and its impact on tumor immunity, which provides an opportunity to optimize prognosis and immune therapy for HCC.
刺猬信号通路的激活与人类肝细胞癌（HCC）的发生和发展相关。然而，其对临床结局和HCC微环境的影响仍不清楚。
我们对一大群HCC患者的刺猬信号通路基因进行了全面分析。具体而言，我们采用单变量Cox回归分析来确定与总生存期相关的刺猬信号通路基因，并使用LASSO算法构建刺猬信号通路相关基因模式。随后，我们使用CIBERSORT和ssGSEA算法研究了刺猬信号通路模式与HCC微环境之间的相关性。此外，肿瘤免疫功能障碍与排除（TIDE）算法和抗PD-L1治疗数据集（IMvigor210）用于评估刺猬信号通路模式在预测免疫检查点抑制剂方面的临床反应。
我们发现基于11个刺猬信号通路基因的预后评分——刺猬信号通路激活评分（HHAS）与HCC患者的生存期显著相关。与低HHAS患者相比，高HHAS患者的生存率明显降低，且HHAS是HCC的一个独立预后因素。功能富集分析揭示了HHAS表型与免疫系统相关功能的关联，进一步研究表明，低HHAS的HCC患者CD8 T细胞中的抗肿瘤免疫激活水平升高，而高HHAS与免疫逃逸表型及免疫抑制细胞浸润增加有关。此外，在IMvigor210的免疫检查点抑制剂（ICI）队列中，HHAS较高的患者ICI治疗效果较差，生存时间缩短，这表明HHAS是预测患者免疫治疗反应的一个有用指标。
总之，我们的研究为推进刺猬信号通路及其对肿瘤免疫影响的研究提供了有价值的见解，这为优化HCC的预后和免疫治疗提供了契机。
