Show simple item record

dc.contributor.authorLiu, David
dc.contributor.authorRegev, Aviv
dc.date.accessioned2020-03-30T11:14:44Z
dc.date.available2020-03-30T11:14:44Z
dc.date.issued2019-06-19
dc.identifier.issn2326-6066
dc.identifier.issn2326-6074
dc.identifier.urihttps://hdl.handle.net/1721.1/124400
dc.description.abstractImmunotherapy with checkpoint inhibitors, such as the programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab, are effective in a variety of tumors, yet not all patients respond. Tumor microsatellite instability-high (MSI-H) has emerged as a biomarker of response to checkpoint blockade, leading to the tissue agnostic approval of pembrolizumab in MSI-H cancers. Here we describe a patient with MSI-H colorectal cancer that was treated with this immune checkpoint inhibitor and exhibited progression of disease. We examined this intrinsic resistance through genomic, transcriptional, and pathologic characterization of the patient's tumor and the associated immune microenvironment. The tumor had typical MSI-H molecular features, including a high neoantigen load. We also identified biallelic loss of the gene for b2-microglobulin (B2M), whose product is critical for antigen presentation. Immune infiltration deconvolution analysis of bulk transcriptome data from this anti-PD-1–resistant tumor and hundreds of other colorectal cancer specimens revealed a high natural killer cell and M2 macrophage infiltration in the patient's cancer. This was confirmed by single-cell transcriptome analysis and multiplex immuno-fluorescence. Our study provides insight into resistance in MSI-H tumors and suggests immunotherapeutic strategies in additional genomic contexts of colorectal cancer.en_US
dc.description.sponsorshipCancer Research UK (C10674/A27140 Grand Challenge Award)en_US
dc.description.sponsorshipEntertainment Industry Foundation. Stand Up to Cancer Colorectal Cancer Dream Team (Grant Number: SU2C-AACR-DT22-17)en_US
dc.language.isoen
dc.publisherAmerican Association for Cancer Research (AACR)en_US
dc.relation.isversionof10.1158/2326-6066.cir-18-0683en_US
dc.rightsCreative Commons Attribution-Noncommercial-Share Alikeen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/en_US
dc.sourcePMCen_US
dc.titleIntrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair–Deficient Colorectal Canceren_US
dc.typeArticleen_US
dc.identifier.citationGurjao, Carino et al. "Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair–Deficient Colorectal Cancer." Cancer immunology research 7 (2019):1230-1236 © 2019 The Author(s)en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Mathematicsen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.relation.journalCancer immunology researchen_US
dc.eprint.versionAuthor's final manuscripten_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2020-02-19T18:38:19Z
dspace.date.submission2020-02-19T18:38:22Z
mit.journal.volume7en_US
mit.journal.issue8en_US
mit.licenseOPEN_ACCESS_POLICY


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record