结肠直肠癌是帮助和阻碍了T细胞
结直肠肿瘤是挤满了白细胞,但这些细胞帮助或阻碍癌细胞是否激烈辩论。尽管一些研究已经表明,白细胞英勇地限制肿瘤的生长和战斗结直肠癌,同样引人注目的证据将白细胞恶性co-conspirators-bolstering肿瘤和帮助传播。
没有w, 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 tumors but, as the disease progresses, undergo biochemical changes and switch sides, strengthening the tumor. The findings,发表在科学, shed further light on the role of T cells in tumor growth, and may open new paths toward colorectal cancer therapies.
“T细胞生活在肠道阻止肿瘤形成,”伯纳德赖斯说,在实验室研究助理的丹尼尔Mucida洛克菲勒大学。“But once tumors form, gut T cell populations change, enter the tumor, and promote tumor growth.”
改变T细胞受体
肠道粘膜可能是身体最脆弱的入境口岸。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着手调查冲突的主张是否这些细胞帮助或阻碍肠道肿瘤的生长。但在生物学通常就是这样,没有简单的答案。
“We had data showing T cells were protective, but the literature suggested that they also promote tumor 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 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. For example, the two categories of T cells boasted different T cell receptors. Moreover, T cells that had entered the tumor produced IL-17, a cytokine that normally promotes inflammation in response to infection. In the tumor microenvironment, however, IL-17 was promoting disease—spurring tumor growth and recruiting other cells to help hide the tumor from the rest of the immune system.
“The T cells had completely changed,” Reis says.
证实了他们的发现,团队然后使用CRISPR基因编辑技术,选择性地去除白细胞的T细胞受体,改变细胞抗肿瘤pro-tumor,反之亦然。通过这种方式,他们设法增加的数量和减少肿瘤在小鼠模型的大小。“When we depleted the original T cells, the mice became sicker,” Reis says. “And when we depleted the tumor invading T cells, the tumors shrank.”
希望人类癌症
Reis and colleagues witnessed similar activity in T cells derived from human colorectal tumors and their environs. Cells inside the tumor resembled the renegade, late-stage 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 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 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 fashion T cells into Trojan horses that can act as anti-cancer cells right inside the tumor microenvironment,” he says.
参考:达西里斯BS, PW,汗工业区,et al。TCR-Vγδ用法区别protumor肠道γδT细胞抗肿瘤的子集。科学。2022,377 (6603):276 - 284。doi:10.1126 / science.abj8695
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