《PANS》：线粒体可增强癌症免疫治疗效果

资讯来源：Will Doss, Northwestern University

编辑翻译：奇奇

译文校对：菁菁

本文献于2021年4月首次刊发在《美国科学院院报》（PANS）上，文献中研究人员发现增强特定细胞的线粒体功能可以使癌症免疫治疗更有效。

根据最近发表在《美国科学院院报》(PNAS)上的一项研究，增强T细胞亚群中的线粒体功能可以使癌症免疫治疗更有效。

与传统的CD4+ T细胞相比，这些NKT细胞（cd1d约束的自然杀伤T 细胞）在发育过程中更依赖于线粒体代谢。该研究的资深作者、微生物免疫学教授Chyung-Ru Wang博士说，在癌症免疫治疗中，该发现让这些细胞成为了一个能增强免疫功能的诱人靶标。研究人员的发现也为科学家增加线粒体的数量提供了可能的途径。

Wang博士也是西北大学Robert H. Lurie综合癌症中心的成员。她说：“如果能够控制细胞的线粒体数量，我们也许能让这些细胞在免疫治疗环境下活得更久。”

传统的T细胞是人体抵御病毒和细菌的主要防线。此外，与传统的T细胞相比，NKT细胞数量较少，但产生的炎症细胞因子却更多。Wang博士说，这就让它们处在一个独特位置，介于先天或直接免疫反应与适应性免疫反应之间。

Wang博士说：“先天性免疫反应在几个小时内就开始了，但是适应性免疫反应可能需要一周多才能确立。通过产生细胞因子和激活其他免疫细胞，这些NKT细胞可以在大约一天内产生反应。”

Wang博士和她的研究团队想要检验T细胞发育的所有差异，这些差异导致两组T细胞之间产生的结果不同。

在研究T细胞中没有线粒体复合物Ⅲ的小鼠时，研究人员发现，虽然常规T细胞依然存在，但是NKT细胞的数量却大大减少，原因是NKT细胞需要更强的T细胞受体信号才能发育，并且需要完整的线粒体活性才能生存。

Wang博士说，这可能是一种防止免疫系统过度激活的体内平衡机制。

但是，在癌症免疫疗法的背景下，保持这些细胞的存活可能会非常有益。由于病原体和人类免疫系统之间的进化竞争，传统的T细胞具有成千上万的抗原靶标。

虽然这能够积极抵抗感染，但也意味着在众多癌症患者中找到一个激活这些T细胞的抗原靶标的可能性极小，因为人与人之间的差异性太大了。

但是，NKT细胞靶向脂质，每个病原体的脂质基本上相同，这意味着可能有一种适用于所有病原体的方法。Wang博士说，有了这些发现，她相信增强线粒体功能也许是在免疫治疗过程中维持这些细胞生存的一种方式，这能够增强免疫反应和之后的抗癌治疗能力。

Wang博士说：“增强这类细胞的线粒体功能可能是让它们在免疫治疗中存活更久的关键。”

英语原文

Mitochondria Could Boost Immunotherapy Effectiveness

Boosting mitochondrial function in a subpopulation of T cells could make cancer immunotherapy more effective, according to a recent study published in the Proceedings of the National Academy of Sciences (PNAS).

Those cells, known as CD1d-restricted natural killer T (NKT) cells, are much more reliant on mitochondrial metabolism during development when compared with conventional CD4+ T cells. That makes those cells an attractive target for boosting immune function in cancer immunotherapy, according to Chyung-Ru Wang, Ph.D., professor of Microbiology-Immunology and senior author of the study, whose findings shedlight on possible routes scientists could take to increase their population.

"If we can manipulate these cells, we might be able to make this cell live longer in an immunotherapy context," said Wang, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Conventional Tcells are the body's main line of defense against viruses and bacteria. On the other hand, NKT cells are less numerous, but produce far more inflammatory cytokines compared to conventional T cells. This places them in a unique position between the innate or immediate immune response and the adaptive immune response, according to Wang.

"Within hours, the innate immune response begins, but the adaptive response can take more than a week to establish," Wang said. "By producing cytokines and activating other immune cells, these NKT cells can produce a response inabout a day."

Wang and her collaborators wanted to examine any differences in T cell development that lead to disparate outcomes among the two groups of T cells.

Studying mice without mitochondria complex III in T cells, the investigators found that while conventional T cells were still present, the population of NKT cells was greatly reduced because NKT cells require stronger signaling from T cell receptors for their development and intact mitochondrial activity for their survival.

This may be a homeostatic mechanism to prevent over-activation of the immune system, according to Wang.

"If these cells never died, they could generate too much immune response," Wang said. "This signaling and metabolic requirement means they die more easily."

However, in a cancer immunotherapy context, keeping these cells alive could be very beneficial. Conventional T cells have thousands of antigen targets, owing to the evolutionary arms race between pathogens and the human immune system.

While this is positive for fighting off infections, this means finding one antigen target that activates these T cells across many patients with cancer is highly unlikely—the variability from person to person is just too high.

However, NKT cellstarget lipids, which are largely the same from pathogen to pathogen—meaning a one-size-fits-all approach may be possible. Armed with these findings, Wang said she believes that boosting mitochondrial function may be one way to sustain these cells over the course of immunotherapy, strengthening immune response and the subsequent cancer-killing ability of the treatment.

"Enhancing mitochondrial function in this type of cells could be the key to making them live longer during immunotherapy," Wang said.

参考文献

Xiufang Weng et al. Mitochondrial metabolism is essential for invariant natural killer T cell development and function, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073/pnas.2021385118

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