Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair-Deficient Colorectal Cancer.
Carino GurjaoDavid R LiuMatan HofreeSaud H AlDubayanIsaac WakiroMei-Ju SuKristen FeltEvisa GjiniLauren K BraisAsaf RotemMichael H RosenthalOrit Rozenblatt-RosenScott RodigKimmie NgEliezer M Van AllenSteven M CorselloShuji OginoAviv RegevJonathan A NowakMarios GiannakisPublished in: Cancer immunology research (2019)
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.
Keyphrases
- single cell
- case report
- rna seq
- dna damage
- stem cells
- end stage renal disease
- high throughput
- gene expression
- cell cycle
- newly diagnosed
- chronic kidney disease
- transcription factor
- oxidative stress
- bone marrow
- cell proliferation
- neoadjuvant chemotherapy
- patient reported outcomes
- mesenchymal stem cells
- locally advanced
- patient reported
- intellectual disability
- epidermal growth factor receptor
- lymph node metastasis
- genetic diversity