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Cancer Immunol Res. 2019 Aug;7(8):1230-1236. doi: 10.1158/2326-6066.CIR-18-0683. Epub 2019 Jun 19.

Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair-Deficient Colorectal Cancer.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
2
Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
3
The Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts.
4
Biotherapeutic and Medicinal Sciences, Biogen, Cambridge, Massachusetts.
5
Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
6
Department of Radiology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
7
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
8
Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
9
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
10
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
11
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Marios_Giannakis@dfci.harvard.edu.

Abstract

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 β2-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 immunofluorescence. Our study provides insight into resistance in MSI-H tumors and suggests immunotherapeutic strategies in additional genomic contexts of colorectal cancer.

PMID:
31217164
PMCID:
PMC6679789
[Available on 2020-02-01]
DOI:
10.1158/2326-6066.CIR-18-0683

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