Activated hedgehog gene pattern correlates with dismal clinical outcome and tumor microenvironment heterogeneity in hepatocellular carcinoma

Limin Zhen; Yi Zhu; Zhen Wu; Jinyao Liao; Liaoyuan Deng; Qianqian Ma; Qili Wu; Gang Ning; Qiuxiong Lin; Liya Zhou; Yanjie Huang; Zewei Zhuo; Ren Chen; Dongnan Yu

doi:10.1016/j.heliyon.2024.e26989

Activated hedgehog gene pattern correlates with dismal clinical outcome and tumor microenvironment heterogeneity in hepatocellular carcinoma

Heliyon. 2024 Feb 28;10(5):e26989. doi: 10.1016/j.heliyon.2024.e26989. eCollection 2024 Mar 15.

Authors

Limin Zhen^{1

2}, Yi Zhu^{1

3}, Zhen Wu^{1

2}, Jinyao Liao², Liaoyuan Deng⁴, Qianqian Ma², Qili Wu⁵, Gang Ning⁶, Qiuxiong Lin⁵, Liya Zhou⁷, Yanjie Huang¹, Zewei Zhuo^{1

4}, Ren Chen², Dongnan Yu³

Affiliations

¹ Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China.
² Department of Infectious Diseases, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China.
³ Department of Anesthesiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China.
⁴ School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China.
⁵ Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China.
⁶ Department of Gastroenterology and Hepatology, Guangzhou Digestive Diseases Center, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, Guangdong Province, China.
⁷ Department of Radiation Oncology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, China.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Clinical outcome; Hedgehog; Hepatocellular carcinoma; Immunotherapy; Tumor immunity.