Researchers Find Genetic Mechanism That Influences Effectiveness of Cancer Immunotherapy

Immunotherapy treatments have proven successful in treating some patients with cancer. Yet, despite this success, most patients do not respond to the treatments. A new study reveals molecular changes within the tumor prevent immunotherapy drugs from killing off the cancer.

Clinical trials with PD-L1 and PD-1 blockade suggested that tumors with a high number of inflammation-causing T cells were more responsive to the immunotherapy-based PD-L1 and PD-1 inhibitors. Tumors with low inflammation, or low T cells, were less responsive. However, what controls T cells in the tumor microenvironment is poorly understood.

"We defined a molecular mechanism to explain why some tumors are inflamed and others are not—and consequently why some patients will be responsive to therapy and others not," said senior author Weiping Zou, MD, PhD, of the University of Michigan Comprehensive Cancer Center in Ann Arbor. The study was published in Nature (2015; doi:10.1038/nature15520).

"If we can reprogram this epigenetic mechanism, then the therapy might work for more patients," said Zou, Charles B. de Nancrede Professor of Surgery, Immunology and Biology at the University of Michigan Medical School.

Zou's group was the first to show expression, regulation, and functional blockade by PD-L1 in dendritic cells in the human cancer microenvironment.

In this study, researchers studied human and mouse models of ovarian cancer cells. They applied epigenetic drugs, which affected DNA methylation, and found that the numbers of T cells in the tumor increased. They also saw that the epigenetic drugs synergized the antitumor effect of PD-L1 blockade in their models.

"We hope this could be developed into a clinical trial testing a combination of PD-L1 and PD-1 blockade with epigenetic therapy. We want to see if we can make the responders more responsive and turn the nonresponders into responders," Zou said.

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