Abstract

Background

The therapeutic potential of immune checkpoint blockade (ICB) extends across various cancers; however, its effectiveness in treating hepatocellular carcinoma (HCC) is frequently curtailed by both inherent and developed resistance.

Objective

This research explored the effectiveness of integrating anlotinib (a broad‐spectrum tyrosine kinase inhibitor) with programmed death‐1 (PD‐1) blockade and offers mechanistic insights into more effective strategies for treating HCC.

Methods

Using patient‐derived organotypic tissue spheroids and orthotopic HCC mouse models, we assessed the effectiveness of anlotinib combined with PD‐1 blockade. The impact on the tumour immune microenvironment and underlying mechanisms were assessed using time‐of‐flight mass cytometry, RNA sequencing, and proteomics across cell lines, mouse models, and HCC patient samples.

Results

The combination of anlotinib with an anti‐PD‐1 antibody enhanced the immune response against HCC in preclinical models. Anlotinib remarkably suppressed the expression of transferrin receptor (TFRC) via the VEGFR2/AKT/HIF‐1α signaling axis. CD8+ T‐cell infiltration into the tumour microenvironment correlated with low expression of TFRC. Anlotinib additionally increased the levels of the chemokine CXCL14, crucial for attracting CD8+ T cells. CXCL14 emerged as a downstream effector of TFRC, exhibiting elevated expression following the silencing of TFRC. Importantly, low TFRC expression was also associated with a better prognosis, enhanced sensitivity to combination therapy, and a favourable response to anti‐PD‐1 therapy in patients with HCC.

Conclusions

Our findings highlight anlotinib's potential to augment the efficacy of anti‐PD‐1 immunotherapy in HCC by targeting TFRC and enhancing CXCL14‐mediated CD8+ T‐cell infiltration. This study contributes to developing novel therapeutic strategies for HCC, emphasizing the role of precision medicine in oncology.

Highlights

Synergistic effects of anlotinib and anti‐PD‐1 immunotherapy demonstrated in HCC preclinical models. Anlotinib inhibits TFRC expression via the VEGFR2/AKT/HIF‐1α pathway. CXCL14 upregulation via TFRC suppression boosts CD8+ T‐cell recruitment. TFRC emerges as a potential biomarker for evaluating prognosis and predicting response to anti‐PD‐1‐based therapies in advanced HCC patients.

Details

Title
Anlotinib potentiates anti‐PD1 immunotherapy via transferrin receptor‐dependent CD8+ T‐cell infiltration in hepatocellular carcinoma
Author
Song, Fei 1 ; Hu, Bo 2 ; Liang, Xiao‐Liang 3 ; Cheng, Jian‐Wen 2 ; Wang, Cheng‐Gui 3 ; Wang, Peng‐Xiang 2 ; Wang, Tian‐Lun 3 ; Tang, Peng‐Ju 3 ; Sun, Hai‐Xiang 2 ; Guo, Wei 4 ; Zhou, Jian 5 ; Fan, Jia 5 ; Chen, Zhong 3 ; Yang, Xin‐Rong 2   VIAFID ORCID Logo 

 Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P. R. China, Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong, P. R. China 
 Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P. R. China 
 Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong, P. R. China 
 Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, P. R. China 
 Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P. R. China, Institutes of Biomedical Sciences, Fudan University, Shanghai, P. R. China 
Section
RESEARCH ARTICLE
Publication year
2024
Publication date
Aug 1, 2024
Publisher
John Wiley & Sons, Inc.
e-ISSN
20011326
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3097385718
Copyright
© 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.