Colorectal tumors are teeming with white blood cells, but whether these cells help or hinder cancer is hotly debated. While some studies have shown that white blood cells heroically restrict tumor growth and fight colorectal cancer, equally compelling evidence presents white blood cells as malignant co-conspirators, bolstering the tumor and helping it to spread.
Now, new research is clarifying the role of these intestinal white blood cells, known as ???????? T-Cells, in colorectal cancer. It turns out that the cells have a double-edged sword: they hold back tumors at an early stage but, as the disease progresses, undergo biochemical changes and switch sides, reinforcing the tumor. The findings, published in La scienceshed more light on the role of ???????? T-cells in tumor growth and might open new avenues for colorectal cancer therapies.
“The T cells that live in the gut work to prevent tumor formation,” says Bernardo Reis, a research associate in Daniel Mucida’s lab at Rockefeller University. “But once tumors form, intestinal T cell populations change, enter the tumor and promote tumor growth. »
Modified T cell receptors
The intestinal mucosa may be the body’s most vulnerable gateway. Composed of a single layer of epithelial cells, this busy digestive region must absorb useful substances like nutrients and expel harmful substances like food-borne pathogens, in a limited working space. ???????? T cells fill in the gaps, perpetually sweeping the epithelium to maintain the integrity of the intestinal lining and prevent pathogens from invading the rest of the body.
Reis set out to investigate conflicting claims regarding whether these cells help or hinder the growth of intestinal tumors. But as is often the case in biology, there was no simple answer.
“We had data showing that T cells were protective, but the literature suggested they also promoted tumor growth,” Reis said. “We wanted to understand what these ‘T cells’ were really doing. »
Working in a mouse model of colorectal cancer, Reis and colleagues derived ???????? T cells from the intestines of animals with early-stage tumors and tumors from mice with advanced cancer. When comparing these two sources of supposedly identical cells, the researchers were surprised to find large molecular differences between them. For example, the two categories of ???????? T-cells possessed different T-cell receptors. Additionally, ???????? T-cells that entered the tumor produced IL-17, a cytokine that normally promotes inflammation in response to an infection. In the tumor microenvironment, however, IL-17 promoted disease – stimulating tumor growth and recruiting other cells to help hide the tumor from the rest of the immune system.
“The T cells ???????? had completely changed,” says Reis.
To confirm their findings, the team then used CRISPR gene-editing technology to selectively remove T-cell receptors from white blood cells, switching cells from anti-tumor to pro-tumor, or vice versa. In this way, they were able to increase the number and decrease the size of tumors in mouse models. “When we depleted the original T cells, the mice got sicker,” Reis says. “And when we exhausted the tumor invading T-cells, the tumors shrank. »
Hope for human cancers
Reis and his colleagues witnessed similar activity in ???????? T cells derived from human colorectal tumors and their surroundings. The cells inside the tumor resembled the renegade, late-stage ???????? T cells seen in mice, while the cells floating around the outside of the tumor looked more like the original Res. “It almost felt like a fight between these two populations,” Reis says. “The regular cells were trying to contain the tumor while the cells inside were promoting tumor growth. »
In the short term, the Mucida lab will focus on strengthening our understanding of what promotes ???????? T cell passage from the ally of the gut to its source of ruin. Future studies will dig deeper, examining whether it might be possible to modulate normal ???????? T cells to curb the tumor and prevent their cancer-promoting alter egos from dominating the arena. Reis is also interested in exploring ways to manipulate the system by which altered ???????? T cells enter the tumor.
“Perhaps we might one day turn T cells into Trojan horses capable of acting as anti-cancer cells directly inside the tumor microenvironment,” he says.
