Determinants of response and intrinsic resistance to pd-1 blockade in microsatellite instability–high gastric cancer

Minsuk Kwon, Minae An, Samuel J. Klempner, Hyuk Lee, Kyoung Mee Kim, Jason K. Sa, Hee Jin Cho, Jung Yong Hong, Taehyang Lee, Yang Won Min, Tae Jun Kim, Byung Hoon Min, Woong Yang Park, Won Ki Kang, Kyu Tae Kim, Seung Tae Kim, Jeeyun Lee

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)


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. Significance: 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.

Original languageEnglish
Pages (from-to)2168-2185
Number of pages18
JournalCancer Discovery
Issue number9
Publication statusPublished - 2021 Sept

ASJC Scopus subject areas

  • Oncology


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