Computational Characterizing Necroptosis Reveals Implications for Immune Infiltration and Immunotherapy of Hepatocellular Carcinoma

Jun Zhu; Tenghui Han; Shoujie Zhao; Yejing Zhu; Shouzheng Ma; Fenghua Xu; Tingting Bai; Yuxin Tang; Yungang Xu; Lei Liu

doi:10.3389/fonc.2022.933210

Computational Characterizing Necroptosis Reveals Implications for Immune Infiltration and Immunotherapy of Hepatocellular Carcinoma

Front Oncol. 2022 Jul 7:12:933210. doi: 10.3389/fonc.2022.933210. eCollection 2022.

Authors

Jun Zhu^{1

2}, Tenghui Han³, Shoujie Zhao⁴, Yejing Zhu⁴, Shouzheng Ma⁵, Fenghua Xu¹, Tingting Bai¹, Yuxin Tang¹, Yungang Xu^{6

7}, Lei Liu¹

Affiliations

¹ Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China.
² Department of General Surgery, The Southern Theater Air Force Hospital, Guangzhou, China.
³ Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
⁴ Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
⁵ Department of Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
⁶ Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.
⁷ Centre for Computational Systems Medicine, School of Biomedical Informatics, The University of Texas Health Science Centre at Houston, Houston, TX, United States.

Abstract

Necroptosis is a programmed form of necrotic cell death in regulating cancer ontogenesis, progression, and tumor microenvironment (TME) and could drive tumor-infiltrating cells to release pro-inflammatory cytokines, incurring strong immune responses. Nowadays, there are few identified biomarkers applied in clinical immunotherapy, and it is increasingly recognized that high levels of tumor necroptosis could enhance the response to immunotherapy. However, comprehensive characterization of necroptosis associated with TME and immunotherapy in Hepatocellular carcinoma (HCC) remains unexplored. Here, we computationally characterized necroptosis landscape in HCC samples from TCGA and ICGA cohorts and stratified them into two necroptosis clusters (A or B) with significantly different characteristics in clinical prognosis, immune cell function, and TME-landscapes. Additionally, to further evaluate the necroptosis levels of each sample, we established a novel necroptosis-related gene score (NRGscore). We further investigated the TME, tumor mutational burden (TMB), clinical response to immunotherapy, and chemotherapeutic drug sensitivity of HCC subgroups stratified by the necroptosis landscapes. The NRGscore is robust and highly predictive of HCC clinical outcomes. Further analysis indicated that the high NRGscore group resembles the immune-inflamed phenotype while the low score group is analogous to the immune-exclusion or metabolism phenotype. Additionally, the high NRGscore group is more sensitive to immune checkpoint blockade-based immunotherapy, which was further validated using an external HCC cohort, metastatic melanoma cohort, and advanced urothelial cancer cohort. Besides, the NRGscore was demonstrated as a potential biomarker for chemotherapy, wherein the high NRGscore patients with more tumor stem cell composition could be more sensitive to Cisplatin, Doxorubicin, Paclitaxel-based chemotherapy, and Sorafenib therapy. Collectively, a comprehensive characterization of the necroptosis in HCC suggested its implications for predicting immune infiltration and response to immunotherapy of HCC, providing promising strategies for treatment.

Keywords: necroptosis; chemotherapy; hepatocellular carcinoma; immunotherapy; tumor microenvironment; tumor-infiltrating cells.