Hepatocellular carcinoma patients with high circulating cytotoxic T cells and intra-tumoral immune signature benefit from pembrolizumab: results from a single-arm phase 2 trial
- Authors
- Hong, Jung Yong; Cho, Hee Jin; Sa, Jason K.; Liu, Xiaoqiao; Ha, Sang Yun; Lee, Taehyang; Kim, Hajung; Kang, Wonseok; Sinn, Dong Hyun; Gwak, Geum-Youn; Choi, Moon Seok; Lee, Joon Hyeok; Koh, Kwang Cheol; Paik, Seung Woon; Park, Hee Chul; Kang, Tae Wook; Rhim, Hyunchul; Lee, Su Jin; Cristescu, Razvan; Lee, Jeeyun; Paik, Yong Han; Lim, Ho Yeong
- Issue Date
- 6-Jan-2022
- Publisher
- BMC
- Keywords
- Carcinoma; Hepatocellular; Pembrolizumab; Biomarkers; Tumor
- Citation
- GENOME MEDICINE, v.14, no.1
- Indexed
- SCIE
SCOPUS
- Journal Title
- GENOME MEDICINE
- Volume
- 14
- Number
- 1
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/136530
- DOI
- 10.1186/s13073-021-00995-8
- ISSN
- 1756-994X
- Abstract
- Background: A limited number of studies have characterized genomic properties of hepatocellular carcinoma (HCC) patients in response to anti-PD-1 immunotherapy. Methods: Herein, we performed comprehensive molecular characterization of immediate (D-42 to D-1) pre-treatment tumor biopsy specimens from 60 patients with sorafenib-failed HCC in a single-arm prospective phase II trial of pembrolizumab. Objective response rate was the primary efficacy endpoint. We used whole-exome sequencing, RNA sequencing, and correlative analysis. In addition, we performed single-cell RNA sequencing using peripheral blood mononuclear cells. Results: The overall response rate of pembrolizumab in sorafenib-failed HCC patients was 10% ([6/60] 95% CI, 2.4-17.6). In a univariate analysis using clinicopathological features, female gender, PD-L1 positivity, and low neutrophil-to-lymphocyte ratio (NLR) were identified as contributing factors to pembrolizumab response. Somatic mutations in CTNNB1 and genomic amplifications in MET were found only in non-responders. Transcriptional profiles through RNA sequencing identified that pembrolizumab responders demonstrated T cell receptor (TCR) signaling activation with expressions of MHC genes, indicating increased levels of T cell cytotoxicity. In single-cell sequencing from 10 pre- and post-treatment peripheral blood mononuclear cells (PBMCs), patients who achieved a partial response or stable disease exhibited immunological shifts toward cytotoxic CD8+ T cells. Conversely, patients with progressive disease showed an increased number of both CD14+ and CD16+ monocytes and activation of neutrophil-associated pathways. Conclusions: Taken together, HCC patients with infiltration of cytotoxic T cells, along with increased active circulating CD8+ T cells during pembrolizumab treatment and down-regulation of neutrophil-associated markers, significantly benefited from pembrolizumab treatment.
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Collections - Graduate School > Department of Biomedical Sciences > 1. Journal Articles
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