한빛사논문
- 조회1,169
Jung Yong Hong1,†, Hee Jin Cho2,3,†, Jason K. Sa4,†, Xiaoqiao Liu5,†, Sang Yun Ha6,†, Taehyang Lee1, Hajung Kim1, Wonseok Kang7, Dong Hyun Sinn7, Geum-Youn Gwak7, Moon Seok Choi7, Joon Hyeok Lee7, Kwang Cheol Koh7, Seung Woon Paik7, Hee Chul Park8, Tae Wook Kang9, Hyunchul Rhim9, Su Jin Lee10, Razvan Cristescu5, Jeeyun Lee1, Yong Han Paik7,11,* and Ho Yeong Lim1,*
1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 2Innovative Therapeutic Research Center, Precision Medicine Research Institute, Samsung Medical Center, Seoul, Republic of Korea. 3Current address: Department of Biomedical Convergence Science and Technology, Kyungpook National University, Daegu, Republic of Korea. 4Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea. 5Merck & Co., Inc., Kenilworth, NJ, USA. 6Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 7Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 8Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 9Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 10Division of Hematology-Oncology, Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Republic of Korea. 11Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea
*Correspondence
†Jung Yong Hong, Hee Jin Cho, Jason K. Sa, Xiaoqiao Liu, and Sang Yun Ha contributed equally to the work as first authors.
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.
논문정보
- Research article
- 2022년 01월 (BRIC 등록일 2022-02-08)
- 국내(교신)+국외 연구진
- 의약학 > 종양의학
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