Immune-related RNA signature predicts outcome of PD-1 inhibitor-combined GEMCIS therapy in advanced intrahepatic cholangiocarcinoma

Tian-Mei Zeng; Yu-Fei Pan; Zhen-Gang Yuan; Dong-Sheng Chen; Yun-Jie Song; Yong Gao

doi:10.3389/fimmu.2022.943066

Immune-related RNA signature predicts outcome of PD-1 inhibitor-combined GEMCIS therapy in advanced intrahepatic cholangiocarcinoma

Front Immunol. 2022 Sep 9:13:943066. doi: 10.3389/fimmu.2022.943066. eCollection 2022.

Authors

Tian-Mei Zeng^{1

2}, Yu-Fei Pan³, Zhen-Gang Yuan², Dong-Sheng Chen⁴, Yun-Jie Song⁴, Yong Gao^{1

5}

Affiliations

¹ School of Medicine, Tongji University, Shanghai, China.
² Department of Oncology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
³ International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
⁴ Jiangsu Simcere Diagnostics Co., Ltd, The State Key Laboratory of Translational Medicine and Innovative Drug Development, Nanjing, China.
⁵ Department of Oncology, Shanghai East Hospital, Shanghai, China.

Abstract

Background: Immune checkpoint inhibitor (ICI)-combined chemotherapy in advanced intrahepatic cholangiocarcinoma has been proved to have more efficacy in a series of clinical trials. However, whether the tumor microenvironment (TME) plays a vital role in immune-combined therapy has not been rigorously evaluated.

Methods: Firstly, we assayed the immunogenic properties of GEM-based chemotherapy. Then, 12 ICC patients treated with PD-1 inhibitor (sintilimab) combined with gemcitabine and cisplatin (GemCis) from a phase 2 clinical trial (ChiCTR2000036652) were included and their immune-related gene expression profiles were analyzed using RNA from baseline tumor samples. Immune-related signature correlating with clinical outcome was identified according to the 12 ICC patients, and its predictive value was validated in an ICC cohort with 26 patients. Multiplexed immunofluorescence (mIF) and flow cytometry (FCM) analysis were performed to evaluate the immune-related molecules with therapeutic outcomes.

Results: GEM-based chemotherapy induced immunogenic cell death of cholangiocarcinoma cells, together with increased CD274 expression. In an ICC cohort, we found that upregulation of immune-checkpoint molecules and immune response-related pathways were significantly related to better clinical outcome. On the contrary, baseline immune-cell proportions in tumor tissues did not show any correlation with clinical benefit between responders and non-responders. Immune-related signature (including six genes) correlating with clinical outcome was identified according to the 12 ICC patients, and its predictive value was validated in a small ICC cohort with 26 patients.

Conclusion: Immune-related RNA signature predicts the outcome of PD-1 inhibitor-combined GEMCIS therapy in advanced intrahepatic cholangiocarcinoma, which could be tested as a biomarker for immune-chemotherapy in the future.

Keywords: immune-related signature; immunochemotherapy; intrahepatic cholangiocarcinoma; prognosis; tumor microenvironment.

MeSH terms

Bile Duct Neoplasms* / drug therapy
Bile Duct Neoplasms* / genetics
Bile Ducts, Intrahepatic / metabolism
Cholangiocarcinoma* / drug therapy
Cholangiocarcinoma* / genetics
Cholangiocarcinoma* / metabolism
Cisplatin / therapeutic use
Clinical Trials, Phase II as Topic
Humans
Immune Checkpoint Inhibitors / therapeutic use
RNA
Tumor Microenvironment

Substances

Immune Checkpoint Inhibitors
RNA
Cisplatin