Determinants of Response and Intrinsic Resistance to PD-1 Blockade in Microsatellite Instability–High Gastric Cancer

  • Minsuk Kwon
    1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • Minae An
    2Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, Korea.
  • Samuel J. Klempner
    3Department of Medicine, Division of Hematology-Oncology, Massachusetts General Hospital, Boston, Massachusetts.
  • Hyuk Lee
    4Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • Kyoung-Mee Kim
    5Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • Jason K. Sa
    6Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Korea.
  • Hee Jin Cho
    7Innovative Institute for Precision Medicine, Samsung Medical Center, Seoul, Korea.
  • Jung Yong Hong
    1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • Taehyang Lee
    1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • Yang Won Min
    4Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • Tae Jun Kim
    4Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • Byung-Hoon Min
    4Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • Woong-Yang Park
    8Samsung Genome Institute, Samsung Medical Center, Seoul, Korea.
  • Won Ki Kang
    1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • Kyu-Tae Kim
    9Department of Physiology, Ajou University School of Medicine, Suwon, Korea.
  • Seung Tae Kim
    1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • Jeeyun Lee
    1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

抄録

<jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>Sequence alterations in microsatellites and an elevated mutational burden are observed in 20% of gastric cancers and associated with clinical response to anti–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 patients with advanced MSI-H gastric cancer 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 antitumor 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. In addition, an 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 gastric cancer and may inform development of strategies to enhance responsiveness.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance:</jats:title> <jats:p>This study highlights response heterogeneity within MSI-H gastric cancer treated with pembrolizumab monotherapy and underscores the potential for extended baseline and early on-treatment biomarker analyses to identify responders. The observed markers of intrinsic resistance have implications for patient stratification to inform novel combinations among patients with intrinsically resistant features.</jats:p> <jats:p>See related commentary by Fontana and Smyth, p. 2126.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 2113</jats:p> </jats:sec>

収録刊行物

  • Cancer Discovery

    Cancer Discovery 11 (9), 2168-2185, 2021-04-12

    American Association for Cancer Research (AACR)

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