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, Scott Rodig, Kimmie Ng, Eliezer M. Van Allen, Steven M. Corsello, Shuji Ogino, Aviv Regev, Jonathan A. Nowak, Marios Giannakis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


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.

Original languageAmerican English
Pages (from-to)1230-1236
Number of pages7
JournalCancer Immunology Research
Issue number8
StatePublished - 2019
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2019 American Association for Cancer Research.


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