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Expression of Endogenous Retroviruses May Explain Response to Immune Checkpoint Therapy in Renal Cell Cancer


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RESULTS OF a new study suggest that expression of endogenous retroviruses may be associated with activation of immune checkpoint pathways in renal cell cancer.1 According to data presented at the 2018 ASCO-SITC Clinical Immuno-Oncology Symposium, abnormal expression of endogenous retroviruses may be beneficial as a biomarker of response to immune checkpoint therapy, particularly in cancers with a low mutational burden.

Shridar Ganesan, MD, PhD

Shridar Ganesan, MD, PhD

“The expression of endogenous retroviruses in tumors appears to be a major mechanism of immunogenicity and can predict responses to programmed cell death protein 1 (PD-1) blockade in clear cell renal cell carcinoma,” said Shridar Ganesan, MD, PhD, Chief of Molecular Oncology and Associate Director for Translational Research of the Rutgers Cancer Institute of New Jersey, who presented this work on behalf of a collaborative research team including the groups of Gyan Bhanot, PhD, at Rutgers Cancer Institute, and W. Kymrin Rathmell, MD, PhD, of Vanderbilt-Ingram Cancer Center. “This may help explain the malignancy’s responsiveness to immune checkpoint inhibition in spite of tumor characteristics, unlike some others that are similarly responsive.”

Gyan Bhanot, PhD

Gyan Bhanot, PhD

W. Kymrin Rathmell, MD, PhD

W. Kymrin Rathmell, MD, PhD

As Dr. Ganesan reported, although increasing mutational burden is generally associated with better responses to immune checkpoint inhibition, there are a few exceptions, including Merkel cell carcinoma and renal cell carcinoma. “Intriguingly, renal cell carcinoma also has a higher response rate to immune checkpoint therapy than would be anticipated by its relatively low mutation burden, but there is no evidence of exogenous viral infection,” said Dr. Ganesan. “So, we turned our attention to endogenous retroviruses, which are an abundant potential stimulant of innate immunity in cancer.”

He explained that endogenous retroviruses represent an ancient integration event. As most of these retroviruses cannot produce all of the proteins necessary for viral replication, they’re essentially “genomic fossils,” he said. However, abnormal expression seen in some human cancers has been associated with evidence of immune activation.

Potential Biomarker

FOR THIS STUDY, Dr. Ganesan and colleagues analyzed RNA-sequencing data from 4,910 tumors across 21 cancers from The Cancer Genome Atlas. The researchers looked to see whether expression of endogenous retroviruses correlated with evidence of immune infiltration and upregulation of checkpoint pathways. After evaluating 66 annotated endogenous retroviruses in the database, they found differing levels of expression in various cancers, but the strongest signal was in clear cell renal cell carcinoma.

“The expression of endogenous retroviruses in tumors appears to be an important mechanism of immunogenicity and may predict responses to PD-1 blockade in clear cell renal cell carcinoma.”
— Shridar Ganesan, MD, PhD

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The researchers then sorted expression of endogenous retroviruses in clear cell renal cell carcinoma into three clusters: high, intermediate, and low expression. A comparison of high- and low-expressing patients showed increased expression of several checkpoint genes, including PD-1, cytotoxic T-lymphocyte–associated protein 4, and lymphocyte-activation gene 3.

Finally, Dr. Ganesan and colleagues analyzed a nonrandom cohort of 15 patients with metastatic clear cell renal cell carcinoma treated with a single-agent immune checkpoint therapy who had either a clearly documented partial response or progressive disease. Using quantitative reverse transcription polymerase chain reaction, the researchers measured the RNA expression of ERV3.2. Compared with nonresponders, ERV3.2 expression was significantly higher in responders (P < .05), Dr. Ganesan reported. The expression of ERV3.2 in particular appears to be associated with response to PD-1 blockade, he noted.

“Abnormal expression of endogenous retroviruses may be a biomarker of response to immune checkpoint therapy in some cancers with low mutation burden, but the mechanism underlying this expression needs to be investigated further,” Dr. Ganesan concluded. ■

DISCLOSURE: Dr. Ganesan is a consultant for Novartis, Roche and Inspirata, where he also holds patents, and his spouse is an employee of Merck.

REFERENCE

1. Panda A, De Cubas A, Beckermann K, et al: 2018 ASCO-SITC Clinical Immuno- Oncology Symposium. Abstract 104. Presented January 27, 2018.


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