The tumor microenvironment is a unique environment that emerges in the course of tumor progression as a result of its interactions with the host. The environment is shaped and dominated by the tumor, and is made up of multiple cell types, including cells of the immune system, such as T lymphocytes and neutrophils.

Most research focuses on T lymphocytes as primary targets of cancer immunotherapy, but new research highlights the importance of focusing our attention on neutrophils. A team of researchers at EPFL’s School of Life Sciences has discovered that the metabolism of neutrophils determines their tumor-supportive behavior in lung cancer development.

Their findings are published in the journal Cancer Research in a paper titled, “Glut1 expression in tumor-associated neutrophils promotes lung cancer growth and resistance to radiotherapy,” and led by Etienne Meylan, PhD, professor at EPFL.

“Neutrophils are the most abundant circulating leucocytes and are essential for innate immunity,” wrote the researchers. “In cancer, pro- or anti-tumor properties have been attributed to tumor-associated neutrophils (TAN). Here, focusing on TAN accumulation within lung tumors, we identify Glut1 as an essential glucose transporter for their tumor supportive behavior.”

The researchers were curious about the fact that cell metabolism in cancer becomes deregulated. Focusing on glucose metabolism in a genetically-engineered mouse model of lung adenocarcinoma, the scientists isolated tumor-associated neutrophils (TANs) and compared them to neutrophils from healthy lungs.

Their findings revealed that the TANs take up and metabolize glucose much more effectively than neutrophils from healthy lungs. The researchers also discovered that TANs express a higher amount of a protein called Glut1, which sits on the cell’s surface and enables increased glucose uptake and use.

“To understand the importance of Glut1 in neutrophils during lung tumor development in vivo, we used a sophisticated system to remove Glut1 specifically from neutrophils,” explained Pierre-Benoit Ancey, PhD, scientist and postdoctoral student and the study’s first author. “Using this approach, we identified that Glut1 is essential to prolong neutrophil lifespan in tumors; in the absence of Glut1, we found younger TANs in the microenvironment.”

The researchers used X-ray microtomography to monitor adenocarcinomas, and found that removing Glut1 from TANs led to lower tumor growth rate but also increased the efficacy of radiotherapy.

“Compared to normal neutrophils, Glut1 and glucose metabolism increased in TANs from a mouse model of lung adenocarcinoma. To elucidate the impact of glucose uptake on TANs, we used a strategy with two recombinases, dissociating tumor initiation from neutrophil-specific Glut1 deletion. Loss of Glut1 accelerated neutrophil turnover in tumors and reduced a subset of TANs expressing SiglecF. In the absence of Glut1 expression by TANs, tumor growth was diminished and the efficacy of radiotherapy was augmented.”

“Usually, we don’t know how to target neutrophils, because they are so important in innate immunity,” said Meylan. “Our study shows that their altered metabolism in cancer could be a new Achilles heel to consider in future treatment strategies. Undoubtedly, we are only beginning to learn about these fascinating cells in cancer.”

Their findings may lead to further research and studies that target tumor-associated neutrophils’ ability to metabolize glucose in lung cancer.

“Our results demonstrate the importance of Glut1 in TANs, which may affect their pro- versus anti-tumor behavior. These results also suggest targeting metabolic vulnerabilities to favor anti-tumor neutrophils,” concluded the researchers.

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