Novel Mechanism of Resistance Identified in Merkel Cell Carcinoma
Posted: Tuesday, October 23, 2018
In a study published in Nature Communications, researchers have identified a novel mechanism of resistance in two patients with metastatic Merkel cell carcinoma. Both initially experienced “dramatic” remissions following treatment with autologous Merkel cell polyomavirus-specific CD8-positive T cells and immune checkpoint inhibitors as a result of dense infiltration of CD8-positive cells into the tumor cells. However, they each suffered late relapses at 18 and 22 months, respectively.
Using single-cell RNA sequencing, Kelly Paulson, MD, PhD, of the Fred Hutchinson Cancer Research Center (Fred Hutch), Seattle, Washington, and colleagues found that human leukocyte antigen–B (HLA-B) had been significantly downregulated by the tumor cells, rendering them undetectable to CD8-positive T cells. This acquired resistance, transcriptional loss of antigen presentation, cannot be detected by traditional methods of immunohistochemical staining. Single-cell RNA sequencing, a relatively new technology, made it possible to pinpoint the potentially reversible escape mechanism.
“It’s absolutely revelatory,” stated senior author Aude Chapuis, MD, also of Fred Hutch, in an institutional press release. “It”s very obvious we need a multipronged approach rather than just one dagger that the cancer can escape.” The researchers concluded that because transcriptional loss of antigen presentation is “likely active in additional tumor types,” it warrants further evaluation in immunotherapy resistance.
