Melanoma Exomes Implicate Antigen-Related Gene Changes in Immunotherapy Resistance

NEW YORK (GenomeWeb) – A Massachusetts General Hospital-led team has found evidence of recurrent antigen presentation gene changes in melanoma tumors that fail to respond — or become resistant — to checkpoint blockade immunotherapy treatments.

The researchers used exome sequencing to track protein-coding profiles in tumor samples taken over time in 17 individuals with metastatic melanoma who were treated with immune checkpoint blockade drugs targeting CTLA4 or PD1. They found that nearly one-third of individuals with acquired resistance or a general lack of response to the checkpoint blockade treatments had alterations affecting B2M, a gene coding for a beta-2-microglobulin contributor to class I antigen presentation by the major histocompatibility complex.

When the team expanded its search to two more cohorts of anti-CTLA4- or anti-PD1-treated melanoma patients, together encompassing 143 individuals, it saw B2M loss-of-heterozygosity in roughly 30 percent of individuals who did not respond to the checkpoint blockade treatments. In treatment responders, on the other hand, such changes appeared about 10 percent of the time. The study appeared online today in Nature Communications.

Based on these and other findings, MGH researchers Nir Hacohen and Ryan Sullivan, the study’s co-corresponding authors, and their colleagues concluded that “B2M loss is a common

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