Deadly low profile

Although a small subset of colorectal cancers that have highly mutated DNA respond briskly to checkpoint inhibitors, most have proved highly resistant to these immunotherapies. A team of researchers led in part by Ludwig Lausanne investigator Michal Bassani-Sternberg applied a technology known as immunopeptidomics to small patient-derived tumors, or organoids, grown in the lab to explore the reason for this resistance. Michal and her team also sought to determine whether resistance could be reversed by treatment with IFN-gamma or MEK inhibitors. They reported in the Journal for ImmunoTherapy of Cancer in November that advanced colorectal cancers display very few neoantigens—mutated protein fragments detected by patrolling T cells—on their surface. This helps explain why immunotherapies that stimulate a T cell attack have not worked well in the majority of advanced CRCs. The researchers looked at five mini-tumors grown from patient samples, which together contained 612 gene mutations that could potentially generate a neoantigen. Only three neoantigens were detected—just a fraction of the number predicted by computational methods. Neither IFN-gamma nor MEK inhibitors improved the presentation of neoepitopes in the organoids.

This article appeared in the April 2020 issue of Ludwig Link. Click here to download a PDF (1 MB).


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