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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 mechanism of intrinsic and acquired resistance to [checkpoint blockade] inhibitors, and should stimulate development of new therapeutic strategies."


The researchers used the Illumina HiSeq 2500 instrument to sequence protein-coding sequences captured from fresh frozen tumor and matched normal samples from 17 metastatic melanoma patients. They also did RNA sequencing on tumor samples to get a look at expression changes in the tumor and tumor microenvironment.

For the seven non-responders, five responders, and five individuals with response followed by resistance, the team considered a set of 49 samples collected before, during, and after treatment with the anti-CTLA4 drug ipilimumab or anti-PD1 treatments such as pembrolizumab or nivolumab.

The researchers narrowed in on the response-related B2M alterations by focusing on genes most frequently affected by loss-of-heterozygosity or other alterations in the non-responder or resistance group. The B2M alterations turned up in tumor samples from three individuals with acquired resistance and two non-responders.

In another 110 melanoma patients treated with anti-CTLA4 immunotherapy and 38 anti-PD1-treated individuals, the team detected B2M loss-of-heterozygosity in 25 of the 86 checkpoint blockade non-responders. Such changes also turned up in a handful of individuals who did respond to the drugs (around 10 percent), and showed significant ties to diminished survival times in both replication cohorts.

The results suggest that class I antigen presentation may have a role in checkpoint blockade immunotherapy response. And based on their follow-up experiments in mouse models of melanoma, the authors saw hints that boosting the activity of the immune system's natural killer cells could combat some of the effects of altering B2M.

"As checkpoint blockade immunotherapy has become a mainstay of cancer therapy," they wrote, "it is imperative that future efforts build upon the work presented here to answer these questions and improve outcomes for our patients."