Non-small–cell lung cancer is the leading cause of death from cancer in the U.S. Immune therapy is providing some patients with essentially a cure for their disease, but a majority of patients don’t respond to immune therapy at all. Predicting which patients can benefit from immune therapy isn’t yet possible. But a researcher now at The University of Texas Southwestern Medical Center hopes to be able to provide some insight.
Cancer biologist Esra Akbay was recruited to the Department of Pathology and Simmons Comprehensive Cancer Center from Dana-Farber Cancer Institute in 2016 with the help of a First-Time Tenure-Track Award from CPRIT. Akbay returns to her Ph.D. alma mater.
Some tumors stimulate the immune system more than others because of the number of mutations they have. Lung cancers, as well as skin and colon cancers, are more immunogenic because these organs are more exposed to carcinogens like smoke, UV light, and carcinogenic foods. The surfeit of mutations and foreign proteins on their surface allow these cancer cells to be recognized as foreign by the immune system, and in theory, more likely be caught. Cancers, however, adopt mechanisms to evade the immune system and escape surveillance.
Akbay is studying the most aggressive form of non-small–cell lung cancer, for which there is currently no targeted therapy. For cancers that have already metastasized, only about 20% of patients who receive chemotherapy plus immune therapy benefit from treatment. Akbay is trying to figure out how to make the other 80% of these cancers more sensitive to immune therapy.
Ironically, she’s found that the therapy-resistant cancers tend to have a high level of background inflammation. The tumor cells are infiltrated by a type of immune cells, called myeloid cells, that can actually interfere with the work of killer T-cells.
Myeloid cells seem to increase the activity of an enzyme, called arginase, that breaks down an amino acid, L-arginine. This amino acid is essential for T-cells. In mice, Akbay is testing a compound that interferes with the function of arginase, in the hopes that it will make T-cells recognize and kill the cancer cells again.
She’s collaborating with lung cancer clinicians at UT Southwestern to see if she can correlate patients who respond poorly to immune checkpoint therapy with high levels of this enzyme in their tumors. She’s also testing the mice to see if feeding them extra L-arginine — a semi-essential amino acid that can be purchased over-the-counter — helps increase the activity of their killer T-cells.
Akbay says it’s unclear why certain tumors have more of these myeloid cells, but she speculates that the lung microbiome may have something to do with it, since myeloid cells are the “first responders” to microbes. “We’d like to think of lung as a sterile place, but it does have its own microbiome,” she says. “Maybe people have different levels of recruitment of myeloid cells. And lung cancer patients especially may have trouble clearing microbes.”
CPRIT support is essential for Akbay’s experiments in mice, testing new drugs, and profiling immune cells in tumors using state-of-the-art technology. All of this can be costly. “You can't study immune therapy in a culture dish,” Akbay says. “You need to look at the immune system of a whole organism.”
Akbay received her undergraduate degree in molecular biology and genetics from Bilkent University in Ankara, Turkey, and her Ph.D. in cancer biology from UT Southwestern. She went to Dana-Farber as a postdoctoral fellow in 2010 and became an instructor there in 2014.
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