A novel immune classification reveals distinct immune escape mechanism and genomic alterations: implications for immunotherapy in hepatocellular carcinoma

Zaoqu Liu; Yuyuan Zhang; Chengcheng Shi; Xueliang Zhou; Kaihao Xu; Dechao Jiao; Zhenqiang Sun; Xinwei Han

doi:10.1186/s12967-020-02697-y

A novel immune classification reveals distinct immune escape mechanism and genomic alterations: implications for immunotherapy in hepatocellular carcinoma

J Transl Med. 2021 Jan 6;19(1):5. doi: 10.1186/s12967-020-02697-y.

Authors

Zaoqu Liu¹, Yuyuan Zhang¹, Chengcheng Shi¹, Xueliang Zhou¹, Kaihao Xu¹, Dechao Jiao², Zhenqiang Sun³, Xinwei Han⁴

Affiliations

¹ Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
² Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China. jiaodechao007@126.com.
³ Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China. zqsun82@csu.edu.cn.
⁴ Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China. fcchanxw@zzu.edu.cn.

Abstract

Background: The tumor immunological microenvironment (TIME) has a prominent impact on prognosis and immunotherapy. However, the heterogeneous TIME and the mechanisms by which TIME affects immunotherapy have not been elucidated in hepatocellular carcinoma (HCC).

Methods: A total of 2195 eligible HCC patients from TCGA and GEO database were collected. We comprehensively explored the different heterogeneous TIME phenotypes and its clinical significance. The potential immune escape mechanisms and what genomic alterations may drive the formation of different phenotypes were further investigated.

Results: We identified three phenotypes in HCC: TIME-1, the "immune-deficiency" phenotype, with immune cell depletion and proliferation; TIME-2, the "immune-suppressed" phenotype, with enrichment of immunosuppressive cells; TIME-3, the "immune-activated phenotype", with abundant leukocytes infiltration and immune activation. The prognosis and sensitivity to both sorafenib and immunotherapy differed among the three phenotypes. We also underlined the potential immune escape mechanisms: lack of leukocytes and defective tumor antigen presentation capacity in TIME-1, increased immunosuppressive cells in TIME-2, and rich in immunoinhibitory molecules in TIME-3. The different phenotypes also demonstrated specific genomic events: TIME-1 characterized by TP53, CDKN2A, CTNNB1, AXIN1 and FOXD4 alterations; TIME-2 characterized by significant alteration patterns in the PI3K pathway; TIME-3 characterized by ARID1A mutation. Besides, the TIME index (TI) was proposed to quantify TIME infiltration pattern, and it was a superior prognostic and immunotherapy predictor. A pipeline was developed to classify single patient into one of these three subtypes and calculated the TI.

Conclusions: We identified three TIME phenotypes with different clinical outcomes, immune escape mechanisms and genomic alterations in HCC, which could present strategies for improving the efficacy of immunotherapy. TI as a novel prognostic and immunotherapeutic signature that could guide personalized immunotherapy and clinical management of HCC.

Keywords: Hepatocellular carcinoma; Immune escape; Immunotherapy; Molecular subtype; Tumor immunological microenvironment.

MeSH terms

Carcinoma, Hepatocellular* / genetics
Carcinoma, Hepatocellular* / therapy
Genomics
Humans
Immunotherapy
Liver Neoplasms* / genetics
Liver Neoplasms* / therapy
Phosphatidylinositol 3-Kinases
Tumor Microenvironment