T Cells Both Attack And Safeguard Colorectal Cancer Tumors

Colorectal tumors are full of white blood cells, but as to whether these cells help or fight against the cancer is still under debate. While certain studies have shown that white blood cells stop tumor growth and fight colorectal cancer, there is equal evidence to show that white blood cells contribute to the spread of cancer as well.

Now, latest research explains the role of these intestinal white blood cells, known as 𝛄 𝛅 T cells, in colorectal cancer. It turns out that the cells have a double-edged functioning, i.e, they rein in early-stage tumors but, as the disease progresses, undergo biochemical changes and switch sides, strengthening the tumor. The findings, which were published in Science, put more light on the role of 𝛄𝛅 T cells in tumor growth, and can open new paths toward colorectal cancer therapies.

Bernardo Reis, a research associate in the laboratory of Daniel Mucida at The Rockefeller University, said of the study, "𝛄𝛅 T cells that live in the gut act to prevent tumor formation. But once tumors form, gut 𝛄𝛅 T cell populations change, enter the tumor, and promote tumor growth."

The intestinal lining may be the body's most vulnerable port of entry. Consisting of 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. The 𝛄𝛅 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 tumors. But as is often the case in biology, there was no simple answer.

Working in a mouse model of colorectal cancer, Reis and colleagues derived 𝛄𝛅 T cells from the intestines of animals with early-stage tumors and from the tumors 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. They found that 𝛄𝛅 T cells had completely changed.

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-tumor to pro-tumor, or vice versa. In this way, they managed to increase the number and decrease the size of tumors in mouse models. "When we depleted the original 𝛄𝛅 T cells, the mice became sicker and when we depleted the tumor invading 𝛄𝛅 T cells, the tumors shrank, he added.

Reis and colleagues witnessed similar activity in 𝛄𝛅 T cells derived from human colorectal tumors and their environs. Cells inside the tumor resembled the renegade, late-stage 𝛄𝛅 T cells seen in mice, while cells hovering around the outside of the tumor 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 tumor while cells inside were promoting tumor growth."

In the short term, the Mucida lab will focus on shoring up our understanding what promotes 𝛄𝛅 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 𝛄𝛅 T cells to curb the tumor and prevent their cancer-promoting alter egos from dominating the arena.

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