한빛사논문
- 조회984
Minsuk Kwon1*, Minae An2*, Samuel J. Klempner3*, Hyuk Lee4*, Kyoung-Mee Kim5*, Jason K. Sa6, Hee Jin Cho7, Jung Yong Hong1, Taehyang Lee1, Yang Won Min4, Tae Jun Kim4, ByungHoon Min4, Woong-Yang Park8, Won Ki Kang1, Kyu-Tae Kim9†, Seung Tae Kim1†, and Jeeyun Lee1,10†
1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
2Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, Korea
3Department of Medicine, Division of Hematology-Oncology, Massachusetts General Hospital, Boston, MA, USA
4Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
5Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
6Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Korea
7Innovative Institute for Precision Medicine, Samsung Medical Center, Seoul, Korea
8Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
9Department of Physiology, Ajou University School of Medicine, Suwon, Korea
10Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan University, Suwon, Korea
*Equal contributing authors
Correspondence to: Kyu-Tae Kim, Ph.D. or Seung Tae Kim, MD or Jeeyun Lee, MD
Abstract
Sequence alterations in microsatellites and an elevated mutational burden are observed in 20% of gastric cancers (GC) and associated with clinical response to anti-programmed death (PD)-1 antibodies. However, 50% of microsatellite instability-high (MSI-H) cancers are intrinsically resistant to PD-1 therapies. We conducted a phase II trial of pembrolizumab in advanced MSI-H GC patients and included serial and multi-region tissue samples in addition to serial peripheral blood analyses. The number of whole-exome sequencing (WES)-derived nonsynonymous mutations correlated with anti-tumor activity and prolonged progression-free survival (PFS). Coupling WES to single-cell RNA sequencing, we identified dynamic tumor evolution with greater on treatment collapse of mutational architecture in responders. Diverse T-cell receptor repertoire was associated with longer PFS to pembrolizumab. Additionally, increase in PD-1+ CD8+ T cells correlated with durable clinical benefit. Our findings highlight the genomic, immunologic, and clinical outcome heterogeneity within MSI-H GC and may inform development of strategies to enhance responsiveness.
논문정보
- Research article
- 2021년 04월 (BRIC 등록일 2021-04-19)
- 국내(교신)+국외 연구진
- 의약학 > 종양의학
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