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

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dc.contributor.authorKwon, M-
dc.contributor.authorAn, M-
dc.contributor.authorKlempner, SJ-
dc.contributor.authorLee, H-
dc.contributor.authorKim, KM-
dc.contributor.authorSa, JK-
dc.contributor.authorCho, HJ-
dc.contributor.authorHong, JY-
dc.contributor.authorLee, T-
dc.contributor.authorMin, YW-
dc.contributor.authorKim, TJ-
dc.contributor.authorMin, BH-
dc.contributor.authorPark, WY-
dc.contributor.authorKang, WK-
dc.contributor.authorKim, KT-
dc.contributor.authorKim, ST-
dc.contributor.authorLee, J-
dc.date.accessioned2023-01-10T00:38:55Z-
dc.date.available2023-01-10T00:38:55Z-
dc.date.issued2021-
dc.identifier.issn2159-8274-
dc.identifier.urihttp://repository.ajou.ac.kr/handle/201003/23845-
dc.description.abstractSequence 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.isoen-
dc.subject.MESHAged-
dc.subject.MESHAged, 80 and over-
dc.subject.MESHAntibodies, Monoclonal, Humanized-
dc.subject.MESHAntineoplastic Agents, Immunological-
dc.subject.MESHBiomarkers, Tumor-
dc.subject.MESHFemale-
dc.subject.MESHHumans-
dc.subject.MESHMale-
dc.subject.MESHMicrosatellite Instability-
dc.subject.MESHMiddle Aged-
dc.subject.MESHNeoplasm Metastasis-
dc.subject.MESHProgrammed Cell Death 1 Receptor-
dc.subject.MESHStomach Neoplasms-
dc.subject.MESHTreatment Outcome-
dc.titleDeterminants of response and intrinsic resistance to pd-1 blockade in microsatellite instability–high gastric cancer-
dc.typeArticle-
dc.identifier.pmid33846173-
dc.contributor.affiliatedAuthorKim, KT-
dc.type.localJournal Papers-
dc.identifier.doi10.1158/2159-8290.CD-21-0219-
dc.citation.titleCancer discovery-
dc.citation.volume11-
dc.citation.number9-
dc.citation.date2021-
dc.citation.startPage2168-
dc.citation.endPage2185-
dc.identifier.bibliographicCitationCancer discovery, 11(9). : 2168-2185, 2021-
dc.embargo.liftdate9999-12-31-
dc.embargo.terms9999-12-31-
dc.identifier.eissn2159-8290-
dc.relation.journalidJ021598274-
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Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
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