Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair–Deficient Colorectal Cancer
Immunotherapy 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, lea...
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| Format: | Article |
| Language: | English |
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American Association for Cancer Research (AACR)
2020
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| Online Access: | https://hdl.handle.net/1721.1/124400 |
| _version_ | 1811083636302151680 |
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| author | Liu, David Regev, Aviv |
| author2 | Massachusetts Institute of Technology. Department of Mathematics |
| author_facet | Massachusetts Institute of Technology. Department of Mathematics Liu, David Regev, Aviv |
| author_sort | Liu, David |
| collection | MIT |
| description | Immunotherapy 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. |
| first_indexed | 2024-09-23T12:36:19Z |
| format | Article |
| id | mit-1721.1/124400 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T12:36:19Z |
| publishDate | 2020 |
| publisher | American Association for Cancer Research (AACR) |
| record_format | dspace |
| spelling | mit-1721.1/1244002022-09-28T08:59:10Z Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair–Deficient Colorectal Cancer Liu, David Regev, Aviv Massachusetts Institute of Technology. Department of Mathematics Massachusetts Institute of Technology. Department of Biology Immunotherapy 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. Cancer Research UK (C10674/A27140 Grand Challenge Award) Entertainment Industry Foundation. Stand Up to Cancer Colorectal Cancer Dream Team (Grant Number: SU2C-AACR-DT22-17) 2020-03-30T11:14:44Z 2020-03-30T11:14:44Z 2019-06-19 2020-02-19T18:38:19Z Article http://purl.org/eprint/type/JournalArticle 2326-6066 2326-6074 https://hdl.handle.net/1721.1/124400 Gurjao, 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 10.1158/2326-6066.cir-18-0683 Cancer immunology research Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research (AACR) PMC |
| spellingShingle | Liu, David Regev, Aviv Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair–Deficient Colorectal Cancer |
| title | Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair–Deficient Colorectal Cancer |
| title_full | Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair–Deficient Colorectal Cancer |
| title_fullStr | Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair–Deficient Colorectal Cancer |
| title_full_unstemmed | Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair–Deficient Colorectal Cancer |
| title_short | Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair–Deficient Colorectal Cancer |
| title_sort | intrinsic resistance to immune checkpoint blockade in a mismatch repair deficient colorectal cancer |
| url | https://hdl.handle.net/1721.1/124400 |
| work_keys_str_mv | AT liudavid intrinsicresistancetoimmunecheckpointblockadeinamismatchrepairdeficientcolorectalcancer AT regevaviv intrinsicresistancetoimmunecheckpointblockadeinamismatchrepairdeficientcolorectalcancer |