The Influence of Immune Heterogeneity on the Effectiveness of Immune Checkpoint Inhibitors in Multifocal Hepatocellular Carcinomas
Open Access
- 15 September 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 26 (18), 4947-4957
- https://doi.org/10.1158/1078-0432.CCR-19-3840
Abstract
Purpose: Immune checkpoint inhibitor therapy is emerging as the promising option for patients with advanced hepatocellular carcinoma. We aimed to investigate the heterogeneity of different tumor nodules of the same patient with multifocal hepatocellular carcinomas in response to immunotherapy and its molecular mechanisms. Experimental Design: We attained 45 surgical tumor samples including 33 small and 12 large nodules from 12 patients with multifocal hepatocellular carcinoma and evaluated genomic and immune heterogeneity among tumors through whole-genome sequencing and RNA sequencing. IHC was performed to validate the expression of immune markers. The responses to anti-programmed cell death protein-1 (PD-1) therapy in patients with multifocal hepatocellular carcinoma were evaluated. Results: The small and large tumors within the same patient presented with similar genomic characteristics, indicating their same genomic origin. We further found the small tumors had higher immune cell infiltration including more CD8(+) T cells, M1 macrophages, and monocytes as compared with large tumors. Besides, the expression of interferon signature predictive of response to anti-PD-1 therapy was significantly upregulated in the small tumors. Moreover, the immune pathways were more vigorous along with less active proliferation pathways in the small tumors. In keeping with this, we found that small nodules were more sensitive to anti-PD-1 therapy than large nodules in patients with multifocal hepatocellular carcinoma. Conclusions: The small tumors in patients with multifocal hepatocellular carcinoma had higher immune cell infiltration and upregulation of immune pathways as compared with the large tumors, which can partially explain the different responses of small and large tumors in the same case to anti-PD-1 therapy.Other Versions
Funding Information
- National Natural Science Foundation of China (81825013, 81771958)
- Bureau of Science and Information Technology of Guangzhou Municipality (201704020215)
- Bureau of Science and Information Technology of Guangzhou Municipality Pearl River S and T Nova Program of Guangzhou (201906010086)
- Guangdong Natural Science Foundation (2019B151502009)
- Bureau of Science and Information Technology of Guangzhou Municipality Guangzhou Research Collaborative Innovation Projects (201704020224)
This publication has 65 references indexed in Scilit:
- InnateDB: systems biology of innate immunity and beyond—recent updates and continuing curationNucleic Acids Research, 2012
- Control-FREEC: a tool for assessing copy number and allelic content using next-generation sequencing dataBioinformatics, 2011
- Nearest Template Prediction: A Single-Sample-Based Flexible Class Prediction with Confidence AssessmentPLOS ONE, 2010
- The patterns and dynamics of genomic instability in metastatic pancreatic cancerNature, 2010
- The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing dataGenome Research, 2010
- ANNOVAR: functional annotation of genetic variants from high-throughput sequencing dataNucleic Acids Research, 2010
- Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1Nature, 2009
- Fast and accurate short read alignment with Burrows–Wheeler transformBioinformatics, 2009
- Focal Gains of VEGFA and Molecular Classification of Hepatocellular CarcinomaCancer Research, 2008
- Sorafenib in Advanced Hepatocellular CarcinomaThe New England Journal of Medicine, 2008