非酒精性脂肪性肝病（NAFLD）影响全球约30%成人。NAFLD包括一系列疾病过程：从非酒精性单纯性肝脂肪变（NAFL），可发展为非酒精性脂肪性肝炎（NASH），逐渐引起肝纤维化，最终可能发展为肝硬化、肝功能衰竭甚至肝细胞癌（HCC）。另一方面，越来越多证据表明NAFLD具有全身性影响，与2型糖尿病、心血管疾病、慢性肾病和某些肝外肿瘤有关，2020年一个国际专家组也提议将NAFLD更名为代谢相关脂肪肝病（MAFLD）。
第57届欧洲肝病研究学会年会（EASL2022）暨2022年国际肝脏大会TM（ILC 2022）上，英国纽卡斯尔大学Helen Reeves教授在“NASH治疗及新药对肝外表现的影响 ”专题会上发表了“NASH和肝外肿瘤”的讲演。《国际肝病》有幸在现场采访了Helen Reeves教授，围绕HCC与中性粒细胞、NAFLD与HCC的全球/亚洲趋势、NASH相关HCC的危险因素、NASH对肿瘤治疗影响相关进展等话题进行阐述。
《国际肝病》
随着肝细胞癌死亡率上升，了解肿瘤免疫轴是关键。循环中性粒细胞升高与包括HCC在内的许多癌症的低存活率有关。了解中性粒细胞数量和行为变化的病理生理学机制和后果可能有助于新的治疗策略。您在大会上分享了一项关于HCC和中性粒细胞的研究壁报，请您谈谈这个研究为临床带来哪些启示？
Helen Reeves教授
中性粒细胞是循环中最常见的白细胞；淋巴细胞是另一种白细胞，具有典型的抗癌特性，但多年来关于许多不同类型癌症的研究表明，中性粒细胞升高，或中性粒细胞/淋巴细胞比值升高，与肝癌患者预后较差有关。中性粒细胞如此“短命”，没有人真的认为它们有特殊的功能性作用，而认为更多与淋巴细胞有关，因为它们寿命略长，并有可能真正杀死癌细胞。
几年前我们开展了一项大型研究，纳入1600例来自英国纽卡斯尔和中国香港的不同病因和不同严重程度的慢性肝病患者。研究表明，在来自东西方的两组患者中，中性粒细胞是预测较差结果的最重要的白细胞，它们与更晚期的肿瘤分期和癌症恶病质有关。在一些患者中，体质差和体重减轻是根治性治疗或姑息治疗的限制因素。因此，我们认为中性粒细胞驱动癌症进展和对癌症的反应，并限制治疗选择。
我们不仅想研究中性粒细胞的数量，还想研究肿瘤中的中性粒细胞，以及中性粒细胞的表型。所有的中性粒细胞都一样吗？循环中性粒细胞与肿瘤和组织中的中性粒细胞相同吗？同时，我们希望找到一些策略来保留中性粒细胞的抗肿瘤特性。如果可以让中性粒细胞攻击肿瘤细胞，但不促使肿瘤发生，也不使影响患者状态使其不适合治疗，那么我们也许就能够利用这些特性来治疗。
我的壁报只描述了组织、肿瘤、肿瘤周围组织中的中性粒细胞，并将其与循环中的情况相关联。我们希望了解外周循环中水平升高并且与较差预后相关的这些中性粒细胞的表型，以及其内在关联的驱动因素。我们近期发表的研究结果表明，中性粒细胞可能是免疫抑制环境的一部分，阻止针对T细胞的检查点抑制剂的作用。如果将阻断PD-1/PD-L1轴的检查点抑制剂与中性粒细胞趋化因子抑制剂联合使用，有可能增加患者对免疫疗法的反应。
这个领域的变化日新月异，希望能在未来的大会上再次和你们探讨。
英文原文：
: As deaths from hepatocellular carcinoma rise, understanding the tumour-immune axis is key. Elevated circulating neutrophils associate with poor survival in many cancers,including HCC. Understanding the pathophysiological mechanisms and consequences of changes in neutrophil numbers and behaviour may aid novel therapeutic strategies. We noticed that you have posted a poster presentation about “hepatocellular carcinoma and neutrophils”could you please tell us your opinion on clinical indications of that study？
Prof. Reeves: We are talking about neutrophils, which are the commonest white blood cell in the circulation. We know that lymphocytes, which are the other white blood cell, are the ones that have the typical anti-cancer properties, but there have been many studies over the years in numerous different types of cancers that have shown that elevated neutrophils, or an elevated neutrophil: lymphocyte ratio, is associated with a poorer prognosis in patients with liver cancer. Neutrophils are such short-lived cells that nobody had really thought that they had a particular functional role, and that it is just more to do with the lymphocytes, because they live a little bit longer and have the potential to actually kill the cancer cells.
What we did was a rather large study a few years ago now, where we had a large population of patients from Newcastle in the north-east, but also some patients from Hong Kong, totaling 1600 patients with different etiologies and different levels of chronic liver disease. In that large study, we were able to show that in both the cohorts of patients from East and West, neutrophils were the most important white cell that predicted poorer outcome. They were associated with more advanced tumor stage. They were associated with cancer cachexia. In some patients, it is actually their poor fitness and weight loss that is the limiting factor for a curative therapy or a palliative therapy. So not only did we think that neutrophils were driving the progression of a cancer, they were driving the response to the cancer, and limiting the therapeutic options.
We wanted to study not just neutrophil numbers, but we wanted to study neutrophils in the tumors themselves. We wanted to study the phenotype of neutrophils. Were all neutrophils the same? Were the neutrophils in the circulation the same as the neutrophils in the tumors and the tissues? And in doing that, we wanted to come up with strategies whereby we could retain the anti-tumor properties of neutrophils. They are the first responders to something abnormal. If we could have neutrophils attacking cancer cells but not promoting the progression of cancer or making our patients less fit for therapy, we would be able to perhaps exploit those properties for therapeutic benefit.
The poster here is just characterizing neutrophils in tissues, in tumors, in the peri-tumor tissues, and correlating that with what goes on in the blood. What is the phenotype that is associated with the elevation in the circulation that is associated with a poorer prognosis? And then looking a little bit at the associations with things that cause the elevation in the circulation and the poorer phenotype in the cancers. Work that actually hasn’t been presented here, but has been recently published, has shown that neutrophils are probably part of the immunosuppressive environment that stops the checkpoint inhibitors that target T-cells working. There is a possibility that if you combine a checkpoint inhibitor that blocks the PD-1/PD-L1 axis with a chemokine inhibitor of neutrophils, we might be able to increase the responses of patients to immunotherapies.
It is a very rapidly changing field, which hopefully I will be able to talk to you about again at future congresses.
《国际肝病》
我们注意到您在会上分享关于NAFLD与HCC的流行病学和监测相关的最新数据，目前NAFLD与HCC的全球/亚洲趋势呈现哪些特点？
Helen Reeves教授
我们在2014年一篇发表于《肝脏病学杂志》（Journal of Hepatology）的文章里表明，在2000年左右，NAFLD相关的HCC甚至还未被承认，而如今，它是我所在的英国北部肝癌最常见的原因。从那时起，这不仅是英格兰北部或是西部的问题。一直有这样的假设，即亚洲的病毒性肝炎是肝病和肝细胞癌的主要原因。从某种程度上来说，确实如此。但NAFLD与肥胖有关，而肥胖是全球流行病，所以现在有非常明确的数据显示，在世界各地，NAFLD相关HCC的发病率都在增加。我们还不确定如何在所有患者群体中进行有效监测和筛查，更不用说不断增长的NAFLD人群了。希望未来几年这种情况会有所改变。
英文原文：
: We have noticed that you will make a presentation on updated epidemiology and surveillance for NAFLD-HCC and are interested in global/Asian trends and challenges of this. Will you walk us through about it？
Prof. Reeves: I think probably the best thing is to come to the session tomorrow, because there is a lot of epidemiology data, and then different international Societies’ Guidelines on how to address surveillance in their different populations. We’ve shown that in the last 10-15 years, NAFLD-HCC wasn’t even a recognized entity in the year 2000, and is now the commonest cause of liver cancer in the north of England where I am from. That was a paper that was published in the Journal of Hepatology in 2014. Since then, it isn’t just a problem in the north of England where I am from, and it isn’t just a problem of the West. There has always been this assumption that it is viral hepatitis in Asia that is the major cause of liver disease and hepatocellular carcinoma. To a certain extent, that is true. But NAFLD is associated with obesity, which is a global epidemic, so now there is very clear data showing that all over the world, there is this increase in the incidence of NAFLD-associated HCC. We haven’t got the answers for how to perform effective surveillance and screening in any patient population, never mind the NAFLD population that is growing. Hopefully, that will change in the coming years.
《国际肝病》
既往研究表明，NASH与某些肝外肿瘤（胃肠癌、乳腺癌等）的风险增加有关。但目前还不确定在NASH个体中患肝外肿瘤风险的大小。据您所知，肝外肿瘤风险升高的个体往往具有哪些特征？对临床有哪些影响？
Helen Reeves教授
事实上，NASH相关HCC的患者是患有代谢综合征的老年患者。他们肥胖、往往合并2型糖尿病并接受胰岛素治疗。这些因素都增加了患各类癌症的风险，不仅仅是HCC。随着年龄增长，他们可能会喝一点酒、吸烟，这些也都是增加癌症风险的因素。计算出NAFLD患者的额外风险有多大，目前有点难。既往研究中清楚显示，主要风险是患HCC的风险。在普通人群中，除了我提到的这些，患其他癌症的风险实际上相对较小。
我认为还没有达到必须对所有NAFLD患者进行结肠镜检查的地步，因为他们患结直肠癌的风险仅略微升高。我们还没有到那一步。对我来说，更重要的是努力理解风险，因为这就有可能干预和延缓患癌的进程。如果我们不了解生物学，就会错过预防的机会。但我不认为这将会影响到不同类型癌症的监测，至少不会超出普通人群目前所能获得的水平。
英文原文：
: We have already known that NASH is associated with an increased risk of developing certain extra‐hepatic cancers including several gastro-intestinal cancers, as well as breast and gynecological cancers. It is currently uncertain which is the magnitude of this cancer risk amongst individuals with NASH. Could you please describe the characteristics of individuals with increased risk of extra‐hepatic cancers and share your opinion with us on How might it impact on clinical practice in the foreseeable future？
Prof. Reeves: The thing is that the patients who develop NASH-associated HCC are older patients with metabolic syndrome. They are obese. They often have type 2 diabetes. They are often treated with insulin, for example. These are things that each elevate the risk of all cancers, not just hepatocellular cancer. As the patients age, they might drink a bit of alcohol, they might smoke - again, these are all things that elevate cancer risk. Trying to work out how much extra risk there is attributed to the patient having NAFLD is a little bit hard. In the studies that have been done, it is very clear that the major risk is for the development of hepatocellular carcinoma. The risk of developing other cancers over and above all of those things I have mentioned in the general population, is actually relatively small.
I don’t think we are reaching the point where we have to perform colonoscopies in all of our NAFLD patients, because they they have a tiny elevated risk of developing colorectal cancer. We are not there yet. What is more important for me, I think, is to try to understand the risk, because there is the potential to intervene and delay the development of cancers. There is an opportunity for prevention that we miss if we don’t understand the biology. But I don’t think there is going to be an impact on surveillance for different types of cancers above and beyond what the general population gets at the moment.
《国际肝病》
我们相信需要进一步的研究来解释NASH和HCC/肝外肿瘤发展之间的复杂联系以及对肿瘤治疗的影响。比如，去年Nature杂志发表了一项研究，表明NASH使得免疫疗法对肝癌治疗无效。有哪些最新进展或您个人的见解？
Helen Reeves教授
你刚才提到的研究是德国癌症研究中心Mathias Heikenwalder小组的一项研究。他们认为，T细胞监视在NASH患者中并没有以正确的方式发生，NASH患者体内环境改变了T细胞功能。这可能对于患癌至关重要，也可能影响对靶向T细胞免疫检查点的免疫疗法的反应能力。NASH患者对这些治疗的反应较弱，仍然有反应，但可能不会像非NASH-HCC患者那样强烈。
我认为我们需要搞清楚一些事，这样我们就可以更恰当地调整治疗方案或采取联合治疗，也许联合一种抑制中性粒细胞的趋化因子抑制剂。这是我们的兴趣所在。但我认为真正关键的是，这些只是尚未真正完成的临床试验的亚分析。Mathias Heikenwalder论文中关于生物学的动物模型是非常好的，但很难将其应用于人体，因为人体试验还没有能力回答这些问题。
阿替利珠单抗和贝伐珠单抗联合治疗在许多国家是一线疗法，检查点抑制剂在一些国家仍是获批的一线治疗药物，在人体研究中，这些药物对所有病因都有效，但可能对NAFLD-HCC患者作用较小，或者有反应的患者比例较小，但仍比以前所用的任何药物都好得多。
所以在这部分患者中还是会使用这些药物。我们治疗患者的方式在未来可能会因不同病因的组合而改变，但目前我们只能使用现有最好的，无论什么病因。
英文原文：
: We believe that further research is needed to explain the complex relationship between NASH and HCC/ extrahepatic cancers development as well as the impact of NASH itself on cancer treatment. For example, a German study published on Nature in 2021 discovered that NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Would you share with us the most lated progresses or your own thoughts on it？
Prof. Reeves: That’s a study from Mathias Heikenwalder’s group. They are suggesting that the T-cells, which are the cells that should be going around picking off tumor cells (the T-cell surveillance), and that doesn’t happen in the right way in patients with NASH. Something about the NASH environment changes the T-cell functionality. That is something that may be important for the development of a cancer, but it is also something that possibly impacts the ability to respond to the immunotherapies that target the T-cell checkpoint. It appears that patients with NASH are less responsive to those treatments. They do still respond, but perhaps not as dramatically as the patient with the non-NASH HCC.
I think that there is something there for us to understand so we can modify therapy or the combination of therapies more appropriately, perhaps in combination with a chemokine inhibitor, which inhibits neutrophils. That is what we are interested in. But I think the real take-home message is that these are sub-analyses of clinical trials that have not really been done. The animal models in Mathias Heikenwalder’s paper looking at the biology were very nice studies, but it is difficult to apply that to a human situation, when the human trials have not been powered to answer those kinds of questions.
I would say, that for the human studies, the combination therapies with atezolizumab/bevacizumab, which is now first-line in many countries, and the checkpoint inhibitors, which in some countries are still approved first-line therapies, work in all etiologies, possibly less so in patients with NAFLD-HCC, or a smaller proportion of patients respond, but they are a heck of a lot better than anything we have had before.
So we don’t want to not use those therapies in that subgroup of patients. The way that we treat patients might change in the future with different combinations for different etiologies, but at the moment, we use the best we have got, and that is the same regardless of etiology.
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