EASL专访丨英国Helen Reeves教授：NASH与肝外肿瘤的趋势、风险与进展

《国际肝病》

Helen Reeves教授

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

<Hepatology Digest>: 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？

《国际肝病》

Helen Reeves教授

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》

Helen Reeves教授

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.