New 研究 Outlines Driver in Immune Cell’s Defense against 黑素瘤

今天在 自然通讯, 亨茨曼癌症研究所的研究人员 犹他大学 report critical new insights into how cells mount an attack against 黑素瘤 肿瘤.

黑素瘤 is an aggressive type of skin cancer that can arise from excess exposure to sun, 频繁的灼伤, 遗传学, 以及其他环境因素. 像所有癌症一样，黑色素瘤起源于细胞内. 经过数十亿年的精心设计和完善, cells are experts at working to root out 和 fix routine errors that arise. A tumor begins when a cell makes faulty copies of itself over 和 over again. 如果任其发展, these faulty cell copies continue to grow into complex ecosystems that become 肿瘤. 一些肿瘤, 像黑素瘤, can go on to develop mechanisms to sustain themselves with blood flow 和 oxygen. They can also send the cancerous cells through the body to proliferate in other organs, 最终导致死亡.

免疫疗法, 是什么训练免疫系统对抗癌细胞, 有时能有效治疗黑色素瘤吗. Some patients experience a long-lasting 和 durable response to immunotherapies. Yet many patients’ 肿瘤 soon learn how to outsmart the drugs.

Underst和ing how cells mount a defense against an aggressive tumor like 黑素瘤 piqued the curiosity of 瑞安·奥康奈尔博士他是HCI的癌症研究员，也是美国国立卫生研究院的病理学教授 大发娱乐. 他的实验室 works to underst和 how 免疫细胞 和 cancer cells interface. He wants to better underst和 the sophisticated metabolic processes within 和 around cells 和 to use those insights to develop more effective cancer therapies.

在这项研究中, O’Connell 和 his team uncovered a key metabolic "switch" driven by an enzyme, 烟酰胺phosphoribosyltransferase, 或NAMPT. They learned how NAMPT plays an important role in how certain 免疫细胞 fight 黑素瘤 肿瘤.

"We were interested in better underst和ing NAMPT because it is increased in specific 免疫细胞 within 肿瘤, 被称为巨噬细胞, 对其他免疫细胞分泌的物质作出反应, 称为干扰素, which is known to be important for effective antitumor responses,奥康奈尔说. O’Connell 和 his team used next-generation RNA sequencing to determine which metabolic genes increase within 免疫细胞 in response to different tumor processes.

“NAMPT是最受欢迎的，”奥康奈尔说. The research team found that a specific inflammatory signaling pathway triggers NAMPT. They discovered that when this inducible NAMPT pathway is disrupted, 细胞的抗肿瘤功能也受到损害.

该研究由 沃伦·沃斯博士, a research assistant professor 和 member of the O’Connell Lab. Voth helped design 和 conduct the experiments to study the role of Nampt 和 also mentored lab trainees who worked on the project. 利用实验室环境下的细胞研究, Voth helped to underst和 how NAMPT is induced in 免疫细胞 和 what happens if the 免疫细胞 block NAMPT induction. The research team then created an experiment using a mouse model system 和 found the same NAMPT pathway was required for the mouse cells to initiate antitumor activity. 接下来，研究小组研究了人类肿瘤的数据 癌症基因组图谱, a federal cancer genomics program that molecularly characterized more than 20,000 primary cancer 和 matched normal samples across 33 cancer types. The critical role of the NAMPT pathway was also a factor in the genomic data they analyzed.

“基于这项工作, we want to underst和 whether novel therapies that enhance the NAMPT pathway in 免疫细胞 in patient 肿瘤 could result in improved outcomes,奥康奈尔说. He hopes the next step will be to underst和 whether therapies that strengthen this pathway in certain 免疫细胞 could be the foundation for more effective treatments. He also wants to underst和 whether high levels of NAMPT in 肿瘤 may predict whether a patient will respond well to some immunotherapies that have inconsistent outcomes.

This work adds to the body of evidence th在 metabolic state of 肿瘤, 免疫细胞, 和 the tumor microenvironment as a whole can have profound impacts on the course of disease by controlling the identity 和 functionality of 免疫细胞 that either fight to destroy the tumor or act to promote cancer growth. O’Connell’s team also found strong evidence that this study has applications to other cancer types.

This work was supported by the National Institutes of Health/National Cancer Institute including P30 CA042014, 和 Huntsman Cancer Foundation via a pilot grant from the 黑素瘤 Disease Center at HCI. O’Connell 和 Voth acknowledge the critical work of the entire research team, 尤其是研究作者托马斯·赫芬顿克, Atakan Ekiz, 和辛迪·芭芭.