恢复疲劳的T细胞，以改善免疫肿瘤治疗

StephenW

Research
Reviving tired T cells to improve immuno-oncology treatments
by Arlene Weintraub | Jun 17, 2019 11:00am
A population of immune cells known as effector T cells are important in the fight against cancer and infectious diseases, because they produce substances that kill the pathogenic cells. Problem is, these T cells can become exhausted.

A team at the University of Pennsylvania has discovered a protein that helps determine the fate of exhausted T cells—and that might be able to be targeted to improve immuno-oncology treatments.

The protein, called TOX, controls the evolution of exhausted T cells. Specifically, high levels of TOX sustained over a long period of time promote the cells’ survival, which may cause cancer to persist or progress, they reported in the journal Nature.


The Penn researchers discovered that the amount of TOX in a T cell orchestrates the body’s response to infections or cancer by controlling the balance of effector T cells and exhausted T cells. Furthermore, TOX shapes the cells’ genomes, making it difficult for some genes to produce proteins. That may explain why it’s so challenging to transform exhausted T cells into effector T cells, they suggested.

Combating T cell exhaustion is of particular interest to researchers developing chimeric antigen receptor T cell (CAR-T) therapies, which involve taking T cells from patients and engineering them so they can recognize and attack their cancers. The technology has been revolutionary in the treatment of certain blood cancers, but it doesn’t work for everyone and it has been difficult to translate to solid tumors—a problem that may be related, in part, to T cell exhaustion.

Several approaches to reviving T cells have been proposed. In February, researchers at the La Jolla Institute for Immunology reported their discovery that removing three proteins called Nr4a transcription factors could reinvigorate exhausted CAR-Ts in rodent studies.

Reviving tired T cells is also of interest to researchers who are trying to improve the response rate to checkpoint-inhibiting drugs like Merck’s PD-1 blocker Keytruda. Scientists at Emory University, for example, have proposed that stimulating an immune protein called CD28 on the surface of T cells could boost responses to PD-1 inhibitors.

Combination treatments could be key in priming T cells so they won’t become exhausted before responding to checkpoint inhibition. Apexigen generated some excitement at the recent American Association for Cancer Research (AACR) meeting for its CD40-activating drug, APX005M, which performed well in pancreatic cancer patients when combined with Bristol-Myers Squibb’s PD-1 inhibitor Opdivo and chemotherapy.

The Penn researchers believe their insights into TOX and its role in shaping T cell identity could be used to develop new immunotherapies.

"The discovery of TOX as the key regulator of exhausted T cells now allows us to envision immunotherapies that target, or engineer, TOX to reverse or prevent exhaustion and improve immunity to infections or cancer," said senior author E. John Wherry, Ph.D., chair of the department of pharmacology and director of Penn's Institute of Immunology, in a statement.

StephenW

研究
恢复疲劳的T细胞，以改善免疫肿瘤治疗
作者：Arlene Weintraub | 2019年6月17日上午11:00
被称为效应T细胞的免疫细胞群在抗击癌症和传染病方面很重要，因为它们产生杀死致病细胞的物质。问题是，这些T细胞会变得疲惫不堪。

宾夕法尼亚大学的一个研究小组发现了一种蛋白质，可以帮助确定疲惫的T细胞的命运，并且可以成为改善免疫肿瘤治疗的目标。

这种名为TOX的蛋白质可以控制疲惫的T细胞的进化。他们在“自然”杂志上报告说，长期持续的高水平TOX可促进细胞的存活，从而可能导致癌症持续存在或进展。


宾夕法尼亚大学的研究人员发现，通过控制效应T细胞和耗尽的T细胞的平衡，T细胞中TOX的数量可以协调身体对感染或癌症的反应。此外，TOX塑造细胞的基因组，使一些基因难以产生蛋白质。他们建议，这可以解释为什么将耗尽的T细胞转化为效应T细胞是如此具有挑战性。

对于开发嵌合抗原受体T细胞（CAR-T）疗法的研究人员而言，对抗T细胞衰竭特别感兴趣，其涉及从患者中取出T细胞并对其进行工程化以使他们能够识别并攻击他们的癌症。该技术在治疗某些血癌方面具有革命性，但它并不适用于所有人，并且难以转化为实体肿瘤 - 这一问题可能部分与T细胞衰竭有关。

已经提出了几种恢复T细胞的方法。 2月，La Jolla免疫学研究所的研究人员报告说，他们发现去除三种叫做Nr4a转录因子的蛋白质可以在啮齿动物研究中重振疲惫的CAR-Ts。

对于那些试图提高对检查点抑制药物如Merck的PD-1阻断剂Keytruda的反应率的研究人员来说，恢复疲倦的T细胞也很有意义。例如，埃默里大学的科学家们提出，在T细胞表面刺激一种名为CD28的免疫蛋白可以促进对PD-1抑制剂的反应。

联合治疗可能是启动T细胞的关键，因此它们在响应检查点抑制之前不会耗尽。 Apexigen最近在美国癌症研究协会（AACR）会议上对其CD40活化药物APX005M产生了一些兴奋，该药物与Bristol-Myers Squibb的PD-1抑制剂Opdivo和化学疗法相结合，在胰腺癌患者中表现良好。

宾夕法尼亚大学的研究人员相信他们对TOX的见解及其在塑造T细胞身份中的作用可用于开发新的免疫疗法。

“TOX作为疲惫T细胞的关键调节因子的发现现在允许我们设想针对或设计TOX的免疫疗法，以逆转或防止疲惫并提高对感染或癌症的免疫力，”资深作者E. John Wherry博士说。 D.，药理学系主任和宾夕法尼亚大学免疫学研究所所长，发表声明。