Colorectal tumours are swarming with white blood cells, but whether these cells help or hinder the cancer is hotly debated.
While some studies have shown that white blood cells heroically restrict tumour growth and combat colorectal cancer, equally compelling evidence casts the white blood cells as malignant co-conspirators—bolstering the tumour and helping it spread.
Now, new research clarifies 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 function: They rein in early-stage tumours but, as the disease progresses, undergo biochemical changes and switch sides, strengthening the tumour.
The findings, published in Science, shed further light on the role of T cells in tumour growth, and may open new paths towards colorectal cancer therapies.
“ T cells that live in the gut act to prevent tumour formation,” says Bernardo Reis, a research associate in the laboratory of Daniel Mucida at The Rockefeller University.
“But once tumours form, gut T cell populations change, enter the tumour, and promote tumour growth.”
Altered T cell receptors
The intestinal lining may be the body’s most vulnerable port of entry.
Composed of but a single layer of epithelial cells, this busy digestive region must absorb useful substances like nutrients, and reject harmful ones like foodborne pathogens, within a limited working space.
T cells mind the gaps, perpetually scanning 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 over whether these cells help or hinder the growth of intestinal tumours.
But as is often the case in biology, there was no simple answer.
“We had data showing T cells were protective, but the literature suggested that they also promote tumour growth,” Reis says.
“We wanted to understand what these T cells were really up to.”
Working in a mouse model of colorectal cancer, Reis and colleagues derived T cells from the intestines of animals with early-stage tumours and from the tumours of mice with advanced cancer.
In comparing these two sources of supposedly identical cells, the researchers were surprised to find vast molecular differences between them.
For example, the two categories of T cells boasted different T cell receptors.
Moreover, T cells that had entered the tumour produced IL-17, a cytokine that normally promotes inflammation in response to infection.
In the tumour microenvironment, however, IL-17 was promoting disease—spurring tumour growth and recruiting other cells to help hide the tumour from the rest of the immune system.
“The T cells had completely changed,” Reis says.
To confirm their findings, the team then used CRISPR gene editing technology to selectively remove T cell receptors from the white blood cells, changing the cells from anti-tumour to pro-tumour, or vice versa.
In this way, they managed to increase the number and decrease the size of tumours in mouse models.
“When we depleted the original T cells, the mice became sicker,” Reis says.
“And when we depleted the tumour invading T cells, the tumours shrank.”
Hope for human cancers
Reis and colleagues witnessed similar activity in T cells derived from human colorectal tumours and their environs.
Cells inside the tumour resembled the renegade, late-stage T cells seen in mice, while cells hovering around the outside of the tumour looked more like the original Res.
“It almost looked like a fight between these two populations,” Reis says.
“Regular cells were trying to contain the tumour while cells inside were promoting tumour growth.”
In the short term, the Mucida lab will focus on shoring up our understanding what promotes T cells’ shift from the intestine’s stark ally into its source of ruin.
Future studies will delve deeper, examining whether it might be possible to modulate normal T cells to curb the tumour 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 tumour.
“Perhaps we might one day fashion T cells into Trojan horses that can act as anti-cancer cells right inside the tumour microenvironment,” he says.
Source: Rockefeller University
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