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Improved cancer therapies may be possible with new insights into the metabolic adaptation of tumors to their environment.

Improved cancer therapies may be possible with new insights into the metabolic adaptation of tumors to their environment.

Newswise — High-grade serous carcinoma is the most aggressive form of ovarian cancer and accounts for the majority of advanced-stage cases. The poor outcomes that are associated with this disease emphasize the need to find more effective treatments. A research team that was led by Kunle Odunsi, MD, PhD, director of the University of Chicago Medicine Comprehensive Cancer Center, has discovered novel metabolic mechanisms that contribute to how ovarian cancer escapes from immune attack, and how combination therapies can exploit these pathways to improve ovarian cancer treatment, as reported in a paper published March 16, 2022, in Science Translational Medicine.

Over the past several years, investigators from the University of Chicago, Roswell Park Comprehensive Cancer Center and other leading institutions have teamed up to address one of the most pressing questions that stymies breakthroughs in the treatment for ovarian cancer— why does immunotherapy for ovarian cancer often fail? They also explored the mechanisms that allow tumors to evade destruction from the immune system.

The researchers focused their efforts on an enzyme called IDO1 (indoleamine 2,3 dioxygenase 1), which is responsible in reducing the amino acid tryptophan. They also created products that could suppress cancer-fighting immune cell (T cells) within the tumor environment. Tumors have learned that T cells are dependent on tryptophan to survive, and they produce high levels of IDO1 to deprive them of tryptophan. Previous research showed that targeting the IDO1 pathway with a drug known epacadostat(EPA) can switch on the tumor’s T cells. IDO1 blockade with immunotherapy alone has had limited success in clinical trials. This suggests a gap in our knowledge of IDO1 biology as well as the consequences of blocking it.

To better understand how ovarian cancer escapes from immune attack, the research team wanted to see exactly what goes on in the tumor microenvironment (TME)—the surrounding normal cells, molecules, and blood vessels that support a tumor’s growth—when IDO1 is blocked. The team began their research in the clinic. They collected tissue samples from patients who had been diagnosed with advanced ovarian cancer. After the patients had received treatment with EPA and surgery to remove their tumors, they collected the samples again.

They conducted experiments in the laboratory to examine the effects of EPA from multiple angles on the TME. Their analysis revealed that EPA was effective at blocking tryptophan’s IDO1 pathway. However, it also revealed that the action triggered a distinct chain of events. The tumor microenvironment responded to these new conditions by redirecting tryptophan breakdown towards the serotonin pathway and increasing nicotinamide-adenine dinucletide production (NAD+). The key factor in reducing anti-tumor T cell activity was NAD+. Understanding anti-tumor immunity can be improved by understanding how NAD+, a key component of key metabolism pathways affects immune responses. 

These results were amazing. The combination of IDO inhibition with EPA and an antagonist drug designed to interfere with the purinergic receptors “rescued” T cell proliferation and led to improved survival in a preclinical mouse model of ovarian cancer. They provide a powerful combination to increase anti-tumor activities.

“These findings highlight the potential downside of IDO1 inhibition and suggest that IDO1 inhibitor therapy will require a combination with NAD+ signaling blockade,” said Odunsi, lead author of the study.

This study is a prime example in translational research. It involves taking observations from the clinic, and then studying them in the laboratory to identify vulnerable therapeutic targets. This study also highlights the benefits of the team science approach. A group of diverse researchers could lead to greater breakthroughs than any one researcher working individually.

“This work represents a highly collaborative effort spanning a broad range of expertise using cutting-edge technologies, from clinical expertise to statistics, metabolism, gene expression, advanced cell characterization and visualization, and a preclinical model of ovarian cancer,” he said. “This body of work encapsulates a tremendous amount of effort, knowledge, and expertise from a total of 36 researchers focused on understanding how we can improve ovarian cancer immunotherapy.”

The study, “Metabolic adaptation of ovarian tumors in patients treated with an IDO1 inhibitor constrains antitumor immune responses,” was supported in part by grants from the National Institutes of Health, National Cancer Institute/Cancer Immunotherapy Network (CITN), the Swiss National Science Foundation, and the American Cancer Society.

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