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Study Reveals How Merkel Cell Carcinoma Eludes Immunotherapy

Killer T cells surrounding cancer cells. Credit: NCI

Researchers at the Fred Hutchinson Cancer Research Center have discovered a source of tumor recurrence in patients with Merkel cell carcinoma who initially show response to immunotherapy treatments. Around 20% of patients with Merkel cell carcinoma experience relapse and subsequent resistance to T-cell therapy. The cause of this relapse remained unknown until the Immunotherapy Integrated Research Center at Fred Hutch more closely examined the molecular changes.

Two patients with Merkel cell carcinoma were administered a combination immunotherapy consisting of a checkpoint inhibitor to bolster the immune system and a T-cell therapy to target and destroy cancer cells. After researchers removed existing T cells from the patients, multiplied them in the lab, then infused them into the patients once again, the cancer cells began to shrink, and the patients' conditions improved. However, in both patients, the cancer returned within 2 years.

To determine what changes occurred within the tumor microenvironment to cause tumor recurrence, the researchers used single-cell RNA sequencing. Findings from the analysis showed that a single gene had been removed from the trio of genes called human leukocyte antigens (HLA), which are targeted by T cells. With the single gene hidden, T cells were no longer able to successfully target the cancer cells.

These results are being followed up with further research to determine which therapeutic combinations will be effective in patients who relapse from initial immunotherapy treatment.

"It's absolutely revelatory," said Aude Chapuis, MD, assistant member of Fred Hutch. "We didn't know what was going on with these patients and how their cancer was able to come back. Now we are able to understand what's going wrong, and that gives us a way to fix it. It's very obvious we need a multi-pronged approach rather than just one dagger that the cancer can escape."

For More Information

Paulson KG, Voillet V, McAfee MS, et al (2018). Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA. Nat Commun, 9(1):3868. DOI:10.1038/s41467-018-06300-3 

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