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

Carino Gurjao, David Liu, Matan Hofree, Saud H AlDubayan, Isaac Wakiro, Mei-Ju Su, Kristen Felt, Evisa Gjini, Lauren K Brais, Asaf Rotem, Michael H Rosenthal, Orit Rozenblatt-Rosen (+8 others)
2019 Cancer immunology research  
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
more » ... gression 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.
doi:10.1158/2326-6066.cir-18-0683 pmid:31217164 pmcid:PMC6679789 fatcat:zrdbe2h66bgfzf2kef6k7oqqau