What Prevents Immunotherapies from Killing Cancer Cells?

Cancer microenvironment may hold the key to increasing immunotherapy drug efficacy.

Cancer microenvironment may hold the key to increasing immunotherapy drug efficacy.

Researchers may be close to determining why some patients with cancer do not respond to treatment with immunotherapy.

Despite the positive results immunotherapies have achieved in treating cancer, the majority of patients fail to achieve a significant response to treatment.

A study published in Nature by the University of Michigan Comprehensive Cancer Center found that molecular changes within the tumor inhibits immunotherapy from eliminating cancer cells.

Prior research has shown that tumors with a high number of inflammation-causing T-cells are more likely to respond to PD-L1 and PD-1 inhibitor immunotherapy. Meanwhile, tumors with low inflammation or low T-cells, were less likely to respond.

Knowledge regarding the underlying mechanism that influences T-cells in the tumor microenvironment is currently limited, however.

"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 study senior author Weiping Zou, MD, PhD. "If we can reprogram this epigenetic mechanism, then the therapy might work for more patients.”

The current study is the first to illustrate the process of PD-L1 expression, regulation, and functional blockade in dendritic cells within the cancer microenvironment, the researchers wrote.

The investigators evaluated both human and mouse models of ovarian cancer cells using epigenetic drugs.

The study showed that T-cells within the tumor increased, while epigenetic drugs synergized the anti-tumor properties of PD-L1 blockade.

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