High-grade serous carcinoma, the most aggressive form ovarian cancer, is responsible for the majority of advanced-stage cases. The poor outcomes of the disease highlight the need for better treatments. Kunle Odunsi MD, PhD, is the director of the University of Chicago Medicine Comprehensive Cancer Center. He has led a research team that discovered new metabolic mechanisms that help ovarian carcinoma escape from immune attack. This paper, published March 16, 2022 in The Journal of Ovarian Cancer, also describes how combination therapies can exploit these pathways for better treatment. Science Translational Medicine.
Roswell Park Comprehensive cancer Center, the University of Chicago and other leading institutions have joined forces to tackle one of the most important questions that prevents any breakthroughs in the treatment of ovarian carcinoma. This is why immunotherapy for ovarian tumors often fails. They focused on the underlying mechanisms of tumors being able evade destruction by immune systems.
The researchers focused their efforts on targeting 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. The tumors produce high levels IDO1 to prevent T cells from getting tryptophan. Previous research has shown that IDO1 blockade drugs, such as epacadostat (EPA), could switch on the tumor-shut off T cells. In paradox, IDO1 blockade combined with immunotherapy has not been successful in clinical trials. This is due to a lack of knowledge about IDO1 biology and its consequences.
The research team wanted a better understanding of how ovarian cancer escapes immune attack. To do this, they studied the tumor microenvironment, which is the surrounding normal cells and molecules that support tumor growth. IDO1 blockage can cause it to be blocked. They began their search in the clinic where they collected tissue samples of patients with advanced ovarian carcinoma who had not been treated with chemotherapy or surgery. After patients had been treated with EPA for two weeks and were removed from the body, they again collected tissue samples.
They conducted experiments in the laboratory to examine the effects of EPA from multiple angles on the TME. They found that EPA was effective in blocking the IDO1 pathway for tryptophan degrading, but that it also triggered a different 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.
The next question was how to make this information more useful in the treatment of ovarian cancer patients. Researchers had an idea. The researchers had a hunch that NAD+ metabolites could attach to purinergic relays that communicate with immune system. They therefore investigated the effect of blocking these receptors upon T cell proliferation and function in an ovarian carcinoma mouse model.
The results were astonishing. Combining IDO inhibition and EPA with an antagonist drug that blocks the purinergic receptors “rescued” cells from proliferation. This resulted in a preclinical mouse model with ovarian carcinoma. They combine to provide a powerful combination that will increase anti-tumor activity.
Odunsi, the study’s principal author, said that the findings highlighted the potential dangers of IDO1 inhibit and suggested that IDO1 therapy will need to be combined with NAD+-signaling blockade.
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 advantages of team science. A group of researchers can lead to more breakthroughs than any one researcher working individually.
He said, “This work represents an extremely collaborative effort spanning a wide range of expertise using cutting edge technologies, from clinical expertise, statistics, metabolism and gene expression to advanced cell characterization, visualization and a preclinical model for ovarian cancer.” This body of work contains a tremendous amount knowledge and expertise from 36 researchers who are all focused on improving ovarian cancer immunotherapy.
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MaterialsProvided by University of Chicago Medical Center. Original written by Jane Kollmer Note: Content can be edited for style or length.