Determinants of Response and Intrinsic Resistance to PD-1 Blockade in Microsatellite Instability-High Gastric Cancer
DC Field | Value | Language |
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dc.contributor.author | Kwon, Minsuk | - |
dc.contributor.author | An, Minae | - |
dc.contributor.author | Klempner, Samuel J. | - |
dc.contributor.author | Lee, Hyuk | - |
dc.contributor.author | Kim, Kyoung-Mee | - |
dc.contributor.author | Sa, Jason K. | - |
dc.contributor.author | Cho, Hee Jin | - |
dc.contributor.author | Hong, Jung Yong | - |
dc.contributor.author | Lee, Taehyang | - |
dc.contributor.author | Min, Yang Won | - |
dc.contributor.author | Kim, Tae Jun | - |
dc.contributor.author | Min, Byung-Hoon | - |
dc.contributor.author | Park, Woong-Yang | - |
dc.contributor.author | Kang, Won Ki | - |
dc.contributor.author | Kim, Kyu-Tae | - |
dc.contributor.author | Kim, Seung Tae | - |
dc.contributor.author | Lee, Jeeyun | - |
dc.date.accessioned | 2022-02-24T22:40:59Z | - |
dc.date.available | 2022-02-24T22:40:59Z | - |
dc.date.created | 2021-12-03 | - |
dc.date.issued | 2021-09 | - |
dc.identifier.issn | 2159-8274 | - |
dc.identifier.uri | https://scholar.korea.ac.kr/handle/2021.sw.korea/136792 | - |
dc.description.abstract | 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. | - |
dc.language | English | - |
dc.language.iso | en | - |
dc.publisher | AMER ASSOC CANCER RESEARCH | - |
dc.subject | IMMUNE MICROENVIRONMENT | - |
dc.subject | TUMORS | - |
dc.subject | MUTATIONS | - |
dc.subject | DIVERSITY | - |
dc.subject | FRAMEWORK | - |
dc.subject | CELLS | - |
dc.title | Determinants of Response and Intrinsic Resistance to PD-1 Blockade in Microsatellite Instability-High Gastric Cancer | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Sa, Jason K. | - |
dc.identifier.doi | 10.1158/2159-8290.CD-21-0219 | - |
dc.identifier.scopusid | 2-s2.0-85107080612 | - |
dc.identifier.wosid | 000693104900024 | - |
dc.identifier.bibliographicCitation | CANCER DISCOVERY, v.11, no.9, pp.2168 - 2185 | - |
dc.relation.isPartOf | CANCER DISCOVERY | - |
dc.citation.title | CANCER DISCOVERY | - |
dc.citation.volume | 11 | - |
dc.citation.number | 9 | - |
dc.citation.startPage | 2168 | - |
dc.citation.endPage | 2185 | - |
dc.type.rims | ART | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Oncology | - |
dc.relation.journalWebOfScienceCategory | Oncology | - |
dc.subject.keywordPlus | CELLS | - |
dc.subject.keywordPlus | DIVERSITY | - |
dc.subject.keywordPlus | FRAMEWORK | - |
dc.subject.keywordPlus | IMMUNE MICROENVIRONMENT | - |
dc.subject.keywordPlus | MUTATIONS | - |
dc.subject.keywordPlus | TUMORS | - |
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