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Gene Discovery May Shed Light on Mechanism of Immunotherapy Resistance

By: Celeste L. Dixon
Posted: Monday, March 19, 2018

Two teams led by scientists at Dana-Farber Cancer Institute in Boston discovered a genetic mechanism that seems to create problematic resistance to immunotherapy in the tumor cells of some patients with kidney cancer and melanoma, potentially establishing new drug targets. Both teams—led by Eliezer M. Van Allen, MD, and Toni K. Choueiri, MD (kidney), and Kai W. Wucherpfennig, MD, PhD, and Shirley Liu, PhD (melanoma)—published their research results recently in Science.

“The findings…might aid efforts to extend the benefits of immunotherapy to more patients and additional types of cancer,” the authors said in a Dana-Farber press release.

A major finding was that changes in a particular group of proteins that regulate how DNA is packaged in cells offer resistance to immune checkpoint blockade. This protein collection is a chromatin remodeling complex called SWI/SNF; its normal function is to “unlock” DNA so it can be read by a cell and activate certain protein-making genes. The genes that encode components of SWI/SNF include ARID2, PBRM1, and BRD7.

The Van Allen/Choueiri team studied patients with metastatic clear cell renal cell cancer who had been treated with nivolumab (n = 35) and similar drugs (n = 63), analyzing their tumor samples with whole-exome DNA sequencing. Patients who had longer survival and progression-free survival, they found, had tumors with no functioning PRBM1 gene. The PRBM1 loss gave rise to expression of other genes, including a pathway called IL6/JAK-STAT3, which helps stimulate the immune system.

The Wucherpfennig/Liu team, using gene-editing CRISPR/Cas9 technology, sought to identify genes in melanoma cells that trigger their resistance to being killed by T cells. They also hit a target in the PRBM1 gene: When they deactivated it in melanoma cells in the lab, the cells’ sensitivity to T cells increased. They also found that when tumors contain mutations in the genes ARID2 and BRD7 in SWI/SNF, they may respond better to checkpoint blockade. 



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