《自然》：对抗肿瘤免疫抑制的新方法

资讯作者：Weill Cornell Medical College

编辑翻译：奇奇

本文献于2021年9月20日发布在国际著名期刊《自然》与《柳叶刀》上。文中来自威尔康奈尔医学院和纽约长老会医院的研究人员发现了一种能够对抗肿瘤免疫抑制的新方法，这将有助于开发肿瘤治疗策略。

通常情况下，恶性肿瘤可以通过抑制附近的抗肿瘤免疫细胞来增强它们自身的生存和扩散能力。最近，一项由威尔康奈尔医学院和纽约长老会医院的研究人员领导的研究发现了一种对抗这种免疫抑制作用的新方法。

放疗(左)或未放疗(右)肺部免疫荧光图像。放射治疗后，棒状细胞分泌更多的抗免疫抑制因子，如分泌标记CC10(黄色)的增加所示。图片来源：Dr. Mittal

在9月20日发表于《自然癌症》杂志上的这项研究中，研究人员确定一组抗免疫抑制因子，这些因子可以由位于肺部气道的棒状细胞分泌。他们在肺癌小鼠模型中发现，这些棒状细胞因子抑制了一种称为髓源性抑制细胞(MDSCs)的强效免疫抑制细胞，肿瘤经常招募这些细胞来帮助它们逃避抗肿瘤免疫反应。

MDSCs的抑制导致肿瘤部位抗肿瘤T细胞数量的增加，极大地提高了FDA批准的PD1免疫疗法的有效性。

合著资深作者Vivek Mittal博士是Neuberger Berman肺癌中心的研究主任和威尔康奈尔医学院心胸外科的研究教授。他说：“这些棒状细胞分泌的因子能够使免疫抑制细胞无效，否则这些细胞就会帮助肿瘤逃避有效的抗肿瘤反应，我们对将这些棒状细胞因子用于癌症治疗的可能性感到兴奋。”

这项研究是近几十年来广泛科学努力的一部分，旨在寻找利用免疫系统对抗癌症方法。这一努力已经产生了“免疫检查点抑制剂”(ICIs)等治疗方法，可以部分消除肿瘤的免疫抑制作用。近年来，肿瘤学家还观察到电离辐射是许多癌症的标准治疗方法，它可以进一步消除这种免疫抑制作用，从而提高ICI治疗的有效性。

在这项新研究中，Mittal博士和资深合著者Nasser Altorki博士（威尔康奈尔医学中心胸外科主任、纽约长老会医院/威尔康奈尔医学院中心主任），以及威尔康奈尔医学院细胞和发育生物学副教授Gao Dingcheng博士，共同研究了辐射是如何增强免疫功能的。

使用非小细胞肺癌（最常见的肺癌形式）的小鼠模型，他们首先证实这种效应在中等剂量的辐射下达到峰值，并导致接受ICI治疗的小鼠在两个月的观察期结束时无肿瘤存活。

研究人员随后发现，辐射通过激活和刺激常驻肺部的棒状细胞的增殖来达到这种效果。众所周知，棒状细胞有助于保护和修复敏感的气道内壁，部分可以减少炎症。

“我们有可能在特定的辐射剂量下看到这些细胞的峰值刺激，因为较低的剂量不会对细胞造成足够的压力，而较高的剂量会杀死它们，”Altorki 博士说。他是 Neuberger Berman肺癌研究中心的主任、David B. Skinner胸外科医学博士、威尔康奈尔医学院Sandra and Edward Meyer癌症中心实验治疗项目负责人。

被激活的棒状细胞会分泌各种分子，研究人员发现，它们可以用8个这种分子组成的“棒状混合物”来替代辐射，并获得基本相同的ICI增强结果。

他们还确定，棒状细胞分子的这种免疫恢复作用源于它们对MDSCs的抑制，而MDSCs长期以来被视为提高癌症免疫疗法疗效的障碍。

为了证实这些实验室发现与人类癌症的相关性，研究人员在一项放射治疗加ICI的临床试验中观察了肺癌患者的血清样本，该试验最近由Altorki博士和他在威尔康奈尔医学院的同事们主持。他们观察到一种被称为CC10的关键棒状混合物分子，该分子的水平在大多数(8例中5例)治疗后改善的患者中显著升高，但在没有改善的患者中(9例中0例)没有升高，这表明CC10可以帮助患者改善。

研究人员现在正在努力确定棒状混合物中哪些分子对抑制MDSCs和加强癌症治疗最重要。他们还计划研究这些棒状细胞分子是否能在其他肿瘤环境中抑制MDSCs。

“我们希望这些分泌的分子不仅能够增强非小细胞肺癌患者的治疗，也能增强其他癌症患者的治疗，这些分子也可以作为预测联合放疗和免疫治疗反应的生物标志物。”Gao博士说，他也是Meyer癌症中心的成员。

英文原文

Scientists Find a New Way to Reverse Immune Suppression in Tumors

Malignant tumors can enhance their ability to survive and spread by suppressing antitumor immune cells in their vicinity, but a study led by researchers at Weill Cornell Medicine and NewYork-Presbyterian has uncovered a new way to counter this immunosuppressive effect.

In the study, published Sept. 20 in Nature Cancer, the researchers identified a set of anti-immunosuppressive factors. They showed in a mouse model of lung cancer that these club cell factors inhibit highly potent immunosuppressive cells called myeloid-derived suppressor cells (MDSCs), which tumors often recruit to help them evade antitumor immune responses.

The inhibition of the MDSCs led to an increase in the number of antitumor T cells at the tumor site, and greatly improved the effectiveness of FDA approved PD1 immunotherapy.

"These club cell-secreted factors are able to nullify immune suppressor cells that otherwise help tumors escape an effective antitumor response," said co-senior author Dr. Vivek Mittal, director of research at the Neuberger Berman Lung Cancer Center and the Ford-Isom Research Professor of Cardiothoracic Surgery at Weill Cornell Medicine. "We're excited by the possibility of developing these club cell factors into a cancer treatment."

The research is part of a broad scientific effort in recent decades to find ways to harness the immune system against cancers. That effort has yielded treatments such as "immune checkpoint inhibitors" (ICIs) which partly undo tumors' immunosuppressive effects. In recent years, oncologists also have observed that ionizing radiation, long a standard treatment for many cancers, can further undo this immune suppression and thereby enhance the effectiveness of ICI treatments.

In the new study, Dr. Mittal and co-senior authors Dr. Nasser Altorki, chief of the Division of Thoracic Surgery at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center, and Dr. Dingcheng Gao, associate professor of cell and developmental biology at Weill Cornell Medicine, teamed up to determine how radiation has this immune-enhancing effect.

Using a mouse model of non-small-cell lung carcinoma, the most common form of lung cancer, they first established that this effect peaked at a moderate dose of radiation, and caused the quadrupling, to 40 percent, of the proportion of ICI-treated mice who survived tumor-free to the end of the two-month observation period.

The researchers then found that radiation has this effect by activating and stimulating the proliferation of lung-resident club cells, which are known to help protect and repair sensitive airway linings, in part by reducing inflammation.

"It's possible that we see a peak stimulation of these cells at a particular radiation dose because a lower dose doesn't stress the cells enough, whereas a higher dose kills them," said Dr. Altorki, who is also director of the Neuberger Berman Lung Cancer Research Center, the David B. Skinner, M. D. Professor of Thoracic Surgery and leader of the Experimental Therapeutics Program of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

The activated club cells secrete various molecules, and the researchers found that they could replace the radiation with a "club cocktail" of eight of these molecules and get essentially the same ICI-enhancing result.

They also determined that this immune-restoring effect of the club cell molecules stems from their inhibition of MDSCs—which have long been seen as an obstacle to the improved efficacy of cancer immunotherapies.

To confirm the relevance of these laboratory findings to human cancers, the researchers looked at blood serum sampled from lung cancer patients in a clinical trial of radiotherapy plus ICI, conducted recently by Dr. Altorki and colleagues at Weill Cornell Medicine. They observed that levels of a key club cocktail molecule, CC10, were significantly elevated in most (5 of 8) of the patients who improved following the treatment, but in none (0 of 9) of the patients who failed to improve—hinting that CC10 can help patients improve.

The researchers now are working to determine which of the molecules in their club cocktail are most important for inhibiting MDSCs and enhancing cancer treatments. They also plan to investigate whether these club cell molecules can inhibit MDSCs in other tumor contexts.

"We hope that these secreted molecules will be able to enhance treatments not just for non-small cell lung cancer patients but for patients with other cancers as well," said Dr. Gao, who is also a member of the Meyer Cancer Center. "These molecules may also be useful as biomarkers predicting the response to combined radiotherapy and immunotherapy."

参考文献

Ban, Y. et al, Radiation-activated secretory proteins of Scgb1a1+ club cells increase the efficacy of immune checkpoint blockade in lung cancer, Nature Cancer (2021).

Nasser K Altorki et al, Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial, The Lancet Oncology (2021).

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