T-cells First Protect Against but then Promote Growth of Colorectal Cancer Tumors, Study Finds

Gamma-delta T-cells undergo a biochemical change that leads them to spur the growth of tumors that previously restricted.

White blood cells, known as gamma-delta T-cells, rein in early-stage tumors but undergo biochemical changes and begin strengthening tumors as colorectal cancer disease progresses, according to research published in Science.

“[Gamma-delta] T-cells that live in the gut act to prevent tumor formation,” said Bernardo Reis, a research associate in the laboratory of Daniel Mucida at The Rockefeller University, in a statement. “But once tumors form, gut [gamma-delta] T-cell populations change, enter the tumor, and promote tumor growth.”

This research clarifies the role of these cells in tumor growth for colorectal cancer, which had been previously debated, with some studies show that gamma-delta T-cells restrict tumor growth and others demonstrating that gamma-delta T-cells bolster tumors and help them spread.

“We had data showing [gamma-delta] T-cells were protective, but the literature suggested that they also promote tumor growth,” Reis said. “We wanted to understand what these [gamma-delta] T-cells were really up to.”

Researchers sought to determine whether gamma-delta T-cells help or hinder the growth of intestinal tumors using a mouse model of colorectal cancer. Researchers derived gamma-delta T-cells from the intestines of animals with early-stage tumors and from the tumors of mice with advanced cancer.

The researchers compared these 2 sources of supposedly identical cells. They were surprised to find vast molecular differences between them.

“The [gamma-delta] T-cells had completely changed,” Reis said in a statement.

The 2 categories of gamma-delta T-cells boasted different T-cell receptors. R2 T-cells that had entered the tumor produced interluekin-17, a cytokine that normally promotes inflammation in response to infection but promoted disease in the tumor microenvironment by spurring tumor growth and recruiting other cells to hide the tumor from the immune system, according to the investigators.

The researchers used CRISPR gene editing technology to confirm their findings. They selectively removed T-cell receptors from the white blood cells to change the cells from anti-tumor to pro-tumor, or vise versa. This allowed the researchers to increase the number and decrease the size of tumors in their mouse models.

“When we depleted the original [gamma-delta] T-cells, the mice became sicker,” Reis explained. “And when we depleted the tumor invading [gamma-delta] T-cells, the tumors shrank.”

Similar activity was observed in gamma-delta T-cells derived from human colorectal tumors and their environs. Cells inside the tumor resembled the renegade, late stage gamma-delta T-cells seen in mice, while cells hovering around the outside of the tumor looked more like the original cells.

“It almost looked like a fight between these two populations,” Reis said. “Regular cells were trying to contain the tumor while cells inside were promoting tumor growth.”

The Mucida lab plans to improve its understanding of what promotes gamma-delta T-cells’ shift from cells that hinder tumors to cells that help tumors. Researchers intend to delve deeper in future studies, examining whether it might be possible to modulate normal gamma-delta T-cells to curb the tumor and prevent the cancer-promoting T-cells from dominating the tumor.

Reis is also interested in exploring ways to manipulate the system by which altered gamma-delta T-cells enter the tumor.

“Perhaps we might one day fashion [gamma-delta] T-cells into Trojan horses that can act as anti-cancer cells right inside the tumor microenvironment,” he said.

The investigators hope this current research and potential future studies may open new paths toward colorectal cancer therapies.

Reference

Colorectal cancer tumors both helped and hindered by T-cells. Rockefeller University. News Release. July 22, 2022. Accessed July 25, 2022. https://www.eurekalert.org/news-releases/959668