Glycans and the Immune System: Understanding Immune Regulation with Prof. Salomé Pinho

Podcast published on 3/1/2023 • Show notes written by Rina Bogdanovic

32 minutes reading time
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Episode summary

Glycans have a great capacity to fine-tune the inflammatory response and often determine how successfully the immune system distinguishes between friend and foe. While cancer cells build a glycan shield to hide from immune surveillance, pathogens can mimic our glycans in order to evade immune detection and perpetuate infection. Salomé Pinho is the Immunology, Cancer and GlycoMedicine Group leader at the Institute for Research and Innovation in Health at the University of Porto, her research focuses on cancer and inflammatory conditions. Listen in as she introduces us to the intricacies of immune regulation and the potential of glycans as diagnostic and prognostic biomarkers as well as immunotherapeutic targets.

Conversation timestamps

We Discuss:

- The role of glycans in immunological tolerance [4:51]

- Why has glycobiology been neglected for so long? [10:28]

- Cancer and immune tolerance [12:08]

- Glycans as cancer biomarkers and immunotherapeutic targets [20:00]

- Glycan mimicry in autoimmune diseases [23:48]

- Glycans as biomarkers of inflammatory bowel disease (IBD) [27:49]

- GlycanSwitch Project [35:33]

About the guest

Articles, books, and other media discussed in the show

Salomé’s research group: Immunology, Cancer & GlycoMedicine

GlycanTrigger Project

GlycanSwitch Project

 

Salomé’s work relevant to this discussion

Glycans as shapers of tumour microenvironment: A sweet driver of T-cell-mediated anti- tumour immune response | Immunology (2022)

Glycans as a key factor in self and nonself discrimination: impact on the breach of immune tolerance | Febs Press (2022)

Bringing to Light the Risk of Colorectal Cancer in Inflammatory Bowel Disease: Mucosal Glycosylation as a Key Player | Inflammatory Bowel Disease (2022)

SARS-CoV-2 Infection Drives a Glycan Switch of Peripheral T Cells at Diagnosis | Journal of Immunology (2021)

Glycans as Immune Checkpoints: Removal of Branched N-glycans Enhances Immune Recognition Preventing Cancer Progression | Cancer Immunology Research (2020)

A [Glyco]biomarker that Predicts Failure to Standard Therapy in Ulcerative Colitis Patients | Journal of Chron’s and Colitis (2018)

Glycosylation in cancer: mechanisms and clinical implications | Nature Reviews Cancer (2015)

Conversation highlights

- The glycosylation profile of a cancer cell is completely different from the glycosylation profile of a normal cell. And this has been demonstrated along years of intensive research that these tumours associated glycans have instrumental roles in each pathophysiological step of tumour development and progression from the very beginning of tumour in its initiation invasion, but also in the metastasis process.

- It's a long-standing debate in glycobiology field, in cancer glycobiology whether the changes in glycosylation are a cause or a consequence of the cancer process. We have evidence supporting that changes in glycosylation can consequently result in cancer development. But we also have evidence that changes in glycosylation can be a consequence of a transformed phenotype. So, we have both evidences supporting both events.

   - So, there is this fine, very tiny little line that separates tolerance and what happens in autoimmunity, what happens in cancer if we look to cancer as an immune suppressive environment.

   - And with GlycanSwitch, we aim to dissect whether the switch that we have evidence that occur at the level of B cells, and this occurs at the level of B cells preceding the development of autoimmune diseases such as rheumatoid arthritis. So, we want to understand when, why, and how this switch on the glycosylation profile of B cells occur, the mechanism behind that, and the way that we could prevent the switch, and at the end by preventing the glycan switch we could prevent the development of rheumatoid arthritis and intercept disease development.

   - We took advantage of our know how on glyco-immunology and specifically on T cells glycosylation. And we decided to essentially screen a cohort of COVID-19 infected individuals, so SARS-CoV-2 infected individuals, and to see what happens to the circulating T cells in terms of the glycosylation profile. So, and making a long story short, what we observed was that infected individuals that develop a worse disease prognosis or developed a severe disease, in comparison with those patients with a mild disease have a different T cell glycosylation profile

Episode transcript

Rina's intro

Rina Bogdanovic [00:04] Hello, hello, and welcome for the first time to GlycanHub - the podcast in which we explore health, disease, and longevity through the lens of glycobiology. My name is Rina, and I am your host – let’s get right into the first episode of this season.

The immune system is the army of the body, armed with artillery which has allowed us to fend off foreign invaders for generations and in the process evolved to distinguish between self and non self, between the tissue of the body and the foreign intruders. However, there are instances, such as in cancer, when the immune system must be able to recognise that what was once a part of the system is suddenly posing a threat. Unfortunately, there are also times where the immune system might mistake healthy tissue as foreign and treat it accordingly. My guest today will introduce us to the intricacies of immune regulation and the role glycans play in the interaction and communication between the immune system and the cells of our body. We’ll discuss how glycans on the surface of our cells act as ID cards as well as how pathogens are able to mimic host glycans in order to evade detection and perpetuate infection. But the central question in the following conversation is what happens when the regulation of immune tolerance falters and the immune system fails to distinguish between friend and foe? My guest today is the Immunology, Cancer and GlycoMedicine Group leader at the Institute for Research and Innovation in Health at the University of Porto as well as the affiliated Professor at Faculty of Medicine. Her research focuses on investigating the role of post-translational modifications by glycosylation in the regulation of key proteins ́ functions involved in cancer and in chronic inflammatory conditions. A warm welcome to Salome Pinho.

Salomé Pinho [02:11] Thank you! Thank you for the kind invitation.

Rina Bogdanovic [02:14] I'm interested in first of all, how did you initially get involved into the field of glycobiology? And what is it about this field that has made you stick around and continue to research?

Salomé Pinho [02:25] Actually, my very first contact with the glycobiology field was at the faculty. But at that time was not a not pretty much explored about the relevance and the impact of the field, only just mentioning that proteins can be decorated with carbohydrates, and we can have glycoproteins, or we can have glycolipids. But in a more specific and in a deeper way, I was involved in the field in my PhD at the University of Porto. So, one of my mentors at that time kindly introduced me to the glycobiology field. And from the very beginning, I get in love about the field, and the many biological and clinical impact that glycans and protein glycosylation can have in health and life sciences in general.

Rina Bogdanovic [03:18] Today, our conversation is going to talk much about basically glycans as the language in our body. And so, I think a good place to start is by maybe having a bit of a visual representation. Most of the time, when we look at illustrations of cells in our bodies, they are shown as very smooth on the outside, when in reality, they are actually very fuzzy. So, could you tell me, what is this fuzz? And what is its purpose?

Salomé Pinho [03:43] The way that we have a visual insight on the surface of a cell. So normally, we have that on textbooks on electronic microscopy view. And actually, we can appreciate that dense and complex coating of something. And that something is glycans, are sugar chains, that form that major biological and physical barrier that occurs between cells and environment. In fact, all of our cells from our body, but also from other organisms, such as virus, bacteria, fungi, all of them are covered with this coating, this shield of glycan structures that arise in the cell surface, giving the visual impression of a kind of a forest. That actually is this fizzy aspect is because of the diversity of glycan structures that arise in a specific place. Yeah. That's why they are so important.

 

The role of glycans in immunological tolerance

Rina Bogdanovic [04:51] Now we are specifically going to be focusing on the role of the immune system and its ability to distinguish between what is home and what is foreign in our body? And this invites this idea of immunological tolerance. Could you explain what we mean by this and how our immune system is able to distinguish between what is self and what is not self.

Salomé Pinho [05:13] So, all of our cells, actually, most of the cells in nature, are covered with glycans, and glycans is actually an evolutionary process. And there is actually this huge diversity of glycan structures that contributes to biological diversity, but also to despeciation. And in fact, each cell in each organism, and I'm talking about we as mammalian or the microorganisms, the parasites, are covered with a unique array of glycans, a glyco signature that acts like an identity card that characterizes a bacteria or characterizes a virus or characterizes, we as mammalian. But, in fact, the glycosylation gene is quite well conserved across evolution. There are significant intra and interspecies variations that actually put glycans as an essential and a fundamental piece of information. And as key molecular determinants able to distinguish self from non self, right. And actually, the first thing that an immune cell sees, is actually glycans. As I mentioned previously, since all of our cells are hidden, or covered, with glycans, the first thing that an immune cell can see to distinguish if the cell is from our body, or is an intruder, are glycans. So that's why glycans are an important piece of information in immune tolerance to guarantee homeostasis. What happens is somehow within a process that is called glycan mimicry, and glycan mimicry is the fact that there are because of evolution, there is some similarity of some glycan structures, some glycoantigens are somehow similar or shared between the host and the parasites. This is the glycan mimicry. And the glycan mimicry actually can be used by the microorganisms by themselves that can engage the glycan mimicry, decorating themselves with glycans from the host that are very similar to the host and distracting the immune system, evading the immune recognition in order to assure infection and to perpetuate the chronic infection. But on the other side, the glycan mimicry also confuses the immune system and for this reason, the immune cells cannot distinguish self from non self because of this glycan similarity. But this glycan similarity can occur also, as a kind of a switch that may contribute to the glycan mimicry and in this way to distract the immune system leading to the inability of the immune cells to promote tolerance, to distinguish the self from non self, and these will consequently result in autoreactive responses, in inflammatory responses, and autoimmunity.

Rina Bogdanovic [08:34] First of all, I really liked your metaphor of glycans on the surface of cells being like ID cards. I've heard people say they're like QR codes or they're like makeup, but essentially, we are saying the same thing. So, one thing I want you before we move on is, you said there are certain similarities between the glycans in mammalian cells and in those of simpler microorganisms, in which ways do they differ?

Salomé Pinho [08:59] During evolution, the complexity of the glycosylation machinery evolved. So, mammalians and humans can actually synthesize very complex glycan structures. We are equipped with such a complex glycosylation machinery, we can extend and elongate the sugar chains, we can terminal sialylate them we can fucosylate them. I mean, there is plenty of diversity in terms of the structures of glycans that humans can synthesize. But on the contrary, microorganisms such as the virus and bacteria are equipped with less complex glycosylation machinery, they are not able to synthesize such complex glycan structures, and essentially the glycans that they can synthesize are less complex, more primitive, not that extended and elongated, and they are mainly high mannosylated glycans. But as I mentioned, there are some structures that are shared, some core structures that are shared between microorganisms, and human beings, that of course, contribute to this process of immune tolerance, or in some situations, the inability, actually, to assure tolerance leading to the process of the branch of immune tolerance.

 

Why has glycobiology been neglected for so long?

Rina Bogdanovic [10:28] As you said, glycans play a crucial role in recognition and tolerance, but they have been for decades very underappreciated when looking at immune regulation. Why do you think this is?

Salomé Pinho [10:42] Yeah, so from many years, I mean, I would say decades ago, glycans were considers simple, sweet decorations of the cell surface, and were actually underappreciated for many years. But also, this is because you have the technological inability to go deeper on the structural characterization and the structural complexity of the glycans that contribute to proteins, it synthesises in a no template driven way. But nowadays, we are in the right moment, technologically speaking, as well. But also, of course, all of the know-how, that was gathered, the compelling body of evidence that were gathered along the years. So, we are actually in a very nice and right position to tackle this complexity. The technology evolved a lot in the last couple of years. So, we are able now to decipher the specific structure of the glycan, where it is attaching in the protein, which carrier proteins are exhibiting these glycans, where at the spatial level the glycans are located in a specific tissue. So yes, the technology evolved a lot. And this of course, contributed to kick off and to foster this field of glycobiology.

 

Cancer and Immune Tolerance

Rina Bogdanovic [12:08] I’m certainly happy to hear that. Now, moving on to thinking more about immune tolerance in terms of cancer. How long ago were changes in glycosylation, first associated with cancer?

Salomé Pinho [12:24] Yes, so the aberrant glycosylation in cancer was first described in the 60s or 70s. I would say more than 50 years ago. It was described as some carbohydrate containing membrane components. And this was essentially I would say the first flag, mentioning that I mean, there are something beyond proteins, genes, and lipids that we need to account for the complexity of cell, of the tissue, of organism, and, of course, the consequences of these in cancer. And in fact, one of the hallmarks of cancer are actually the changes in the glycosylation profile. The glycosylation profile of a cancer cell is completely different from the glycosylation profile of a normal cell. And this has been demonstrated along years of intensive research that these tumour associated glycans have instrumental roles in each pathophysiological steps of tumour development and progression from the very beginning of tumour in its initiation invasion, but also in the metastasis process.

Rina Bogdanovic [13:32] Now, thinking back on the ID card, as you said, the glycans change in the cancerous cells compared to healthy cells. So, we would imagine the ID card also changes and yet cancer is still able to evade the immune system. Why is this?

Salomé Pinho [13:47] Actually yes, this is one of the concepts of immune evasion that give rise to this revolutionised field of research and clinical applicability of the immunotherapy that was actually the basis for the Nobel prize. Because we know that in cancer and in the vicinity of the tumour cells, there is a clear, immune suppressive and immune regulatory network that allows and fosters cancer development and progression. And of course, glycans have been described by others and us, to be important in this interplay between cancer cells and the surrounding immune system. For example, what we demonstrated was the fact that there are specific types of glycan structures that has been widely described by others and us, to be tumour associated glycans with overexpression in a variety of epithelial tumours, such as, for example, the complex branched N-glycans. And what we demonstrated was that this layer of complex branched glycans that are exposed at the cancer cell surface, serves as a glycan shield that protects the cancer cells and hide them from the immune surveillance. And what we found was that when we remove this glycan mask, we were able to expose other immunogenic epitopes allowing a proper immune surveillance by the immune system. So, actually glycans are essential in the interplay here, between the cancer cells, but also with the immune system. And this is essentially because this is I think, this is an important information, this interplay that exists between tumour expressing glycans and tumour cells that express aberrant glycans and immune system and not only in cancer, but also in inflammatory and autoimmune processes. This interplay with the immune system is essentially because immune cells are equipped with such a variety of glycan sensing receptors. And here I'm talking about the C-type lectins, the galectins and so on that equip immune cells with the capacity to sense the glycosylation alterations mounting either pro inflammatory or anti-inflammatory responses. So essentially, this creates a glycan hub, a network between cells that express different types of glycan structures and immune cells that are able to send, detect, recognize and instruct depending on the glycans that they are sensing and recognizing a proinflammatory response or an anti-inflammatory response. And if we are talking about the example of cancer, if an anti-inflammatory or regulatory response is mounted, this promotes cancer development. So, if through glycans engineered or glycosylation reprogramming, we're able to promote the exposure of other immunogenic glycans, recognized by the immune cells, to multiply inflammatory response will potentiate an effective and superior anti tumour immune response.

Rina Bogdanovic [17:20] Glycans in cancer, and glycans in healthy cells, do differ and that does impact whether the pro inflammatory or anti-inflammatory response is going to be stimulated. But do we understand the reason why there is a shift from a normal glycosylation pathway in these cancerous cells?

Salomé Pinho [17:37] What happens is that protein glycosylation is important in homeostatic pathways. So, they are important molecular pieces to assure a homeostatic environment and changes in these changes in glycosylation occur in response to environmental or genetic stimuli that essentially lead to a glycan switch. In cancer, what happens as I mentioned, the change in glycosylation is a hallmark of cancer. And these changes can be due to many factors. There are specific signalling pathways that are occurring in the cell associated with the cancer development process. And these signalling pathways are described to instruct the transcription of specific glyco-genes and to alter the glycosyltransferase profile in a specific cell and these will consequently result in changes in the glycosylation profile. But there are other factors for example, the immune environment and specific cytokines may also contribute to change the glyco-transcriptomic profile in a specific cell leading to consequently to changes in the glycosylation profile. Another example, the pH that I would say the physical pathological conditions of the cell for example, the pH of the cell can also contribute to alter the organization and the molecular assembly of the glycosyltransferases in the Golgi. And these will consequently have an impact alterations of the glycosylation profile. However, it's a long-standing debate in glycobiology field, in cancer glycobiology whether the changes in glycosylation are a cause or a consequence of the cancer process. We have evidence supporting that changes in glycosylation can consequently result in cancer development. But we also have evidence that changes in glycosylation can be a consequence of a transformed phenotype. So, we have both evidences supporting both events.

 

Glycans as cancer biomarkers and immunotherapeutic targets

Rina Bogdanovic [20:00] Now thinking of early detection and glycans being used as potential biomarkers of cancer, looking at your work with colorectal cancer, how early on were you able to spot glycans associated with cancer?

Salomé Pinho [20:14] What we found was that these changes in the glycosylation profile of cancer cells, we have evidences that this might occur quite early in the process of carcinogenesis. For example, what we demonstrated, and we published was, for the branched glycans catalysed by the GnT5 glycosyltransferase, which is encoded by the Mcat5 glyco-gene, we found the gradual overexpression of these branched glycan structures along the colon carcinogenesis process. But it was very clear, the observation that the highest levels of abnormal expression of this branched glycans was observed as early as in pre-malignancy at the level of dysplasia, which is a premalignant condition. And this, of course, raises and opens a handful of many other questions about the relevance of these glycans and changes in glycosylation in early detection of cancer, and in the prevention of cancer development, and that is something that we are exploiting in the group.

Rina Bogdanovic [21:23] Do you think cancer associated glycans can be used as potential immunotherapeutic targets?

Salomé Pinho [21:30] Yes, I mean, I think the concept of glyco-medicine is gaining more and more power and impact in oncology, but also in other fields such as in immunity. Because I mean, not only because, as I mentioned, there is this unique array of glycans that characterizes both homeostatic but also a pathological condition. And this glycan switch that may occur associated with altered phenotypes associated with disease. So, these can serve as glyco- biomarkers. The signature that I mentioned previously, and we have evidences that not only for example, in inflammatory bowel disease, but also in systemic lupus erythematosus that the profile of glycans detected, for example, at diagnosis of a specific disease can have prognostic value; can actually serve as a biomarker for prognosis for predicting, for example, response to therapy. The same holds true when we talk about serum levels of, for example, glycoproteins and I'm talking about IgG glycosylation. More and more evidence is showing that the pattern of antibodies glycosylation detected in serum can predict the development of inflammatory and autoimmune diseases. We have the example of rheumatoid arthritis, there was a seminal paper showing that there is a change in the glycosylation profile of IgG that precede the onset of rheumatoid arthritis. So not only as a source of biomarkers, but I truly believe that they can act as a target for therapeutic intervention. So, the power of glycosylation reprogramming, envisioning to achieve homeostasis, I think it's immense. And we are I mean, on the top of the iceberg, and of course, we have plenty of opportunities to study the power of glycans as immune therapeutic strategies. Because the power of glycans to fine-tune the inflammatory response is very strong.

 

Glycan mimicry in autoimmune diseases

Rina Bogdanovic [23:48] That's amazing to hear, because as someone who has autoimmune conditions, I know how limited our current therapeutic options are. But thank you for segueing us to autoimmunity. You have talked previously about how pathogens can take advantage of glycan mimicry to confuse our immune system. And very often as a consequence, people might end up with having autoreactive reactions, so do glycans on the tissues in our body, which are the target for autoimmunity, do those glycans resemble the ones on pathogens? Is there a similarity between those in people with autoimmune diseases?

Salomé Pinho [24:24] We have evidence for example in lupus that it occurs very specifically on lupus patients with kidney olfaction and having an inflammation in the kidney that we call glomerular nephritis or lupus nephritis. We show it that in lupus nephritis patients there is a clear glycan switch and the glycan switch goes towards an array of glycans expressed at the surface of kidney cells that is very close to what happens in microorganisms. So, we found a microbiome associated glyco-signature that of course, engage in this process of glycan mimicry, and we have now evidences that these glycans switch towards this glycan mimicry. So, there is a kind of glycome-signature that confounds the immune system and distracts them, leading to this branch of immune intolerance. And we have evidence that in fact, this glycan switch promotes directly the activation of the immune system towards autoreactive responses. And we have that evidence is in lupus, but there are of course, other diseases where that might occur as well. Actually, on that regard we were quite recently funded by the European Commission, with a project that aims to tackle the relevance of the mucosa glycome in the context of inflammatory bowel disease development. And the way that this mucosa glycome is relevant, there's a master trigger from health to intestinal inflammation transition. This is the GlycanTrigger Project that we are just starting, and we're sponsored and funded by the European Commission aiming precisely to tackle the role of these glycocalyx and mucosa glycome composition as an essential piece that might trigger the health to intestinal inflammation transition.

Rina Bogdanovic [26:26] Now, that sounds incredibly exciting, what are the goals of this project? If you could summarize quickly.

Salomé Pinho [26:32] Yeah, the goal is exactly that. One, so, there is a clear shift between health and intestinal inflammation, this is associated with chronic inflammatory processes, inflammatory bowel disease is one of them. So IBD, that comprises both Crohn's disease and ulcerative colitis are two major chronic inflammatory disorders with a very important incidence in young populations in the active period of life. So we essentially we will decipher the role of mucosal glycosylation to glycocalyx as an early event that might promote and trigger a prime inflammatory response, the way that it impacts the microbiota composition, the way that it would trigger important hubs at the level of the intestinal mucosa, important immunological players that will be activated leading to the transition process from healthy to inflammation, the way that this could be translated in a biomarker for disease prevention, and eventually as a target to prevent disease initiation. That's the main goals of the project.

 

Glycans as biomarkers of inflammatory bowel disease (IBD)

Rina Bogdanovic [27:49] That sounds amazing. I'm particularly curious about thinking in context of the relation to the microbiota in IBD. That's going to be very interesting to read about. But thinking of IBD and your previous work, what have you found already in terms of what happens to glycans in patients with IBD? And how early on can we spot these differences?

Salomé Pinho [28:11] What we found on IBD was actually in the model of ulcerative colitis patients, we showed a clear glycosylation alteration but specifically at the level of infiltrating T lymphocytes. So, I mean, essentially, all of the chronic inflammatory diseases and autoimmune diseases are characterized by these huge infiltration of inflammatory cells, namely T cells. And what we found was that in the level of intestinal mucosa, we found the deficiency on a specific glycan structure on C3+T cells, and these abnormal T cell glycoforms that infiltrate the mucosa, were responsible for a hyperactive immune response that is associated with the severity of the disease. So essentially, we show it also that we could metabolically glyco-reprogram this glycosylation profile of mucosal T lymphocytes, in restoring of course, the homeostasis and achieving immune control. And this, of course, also set the ground for the possibility of testing these in a clinical trial. Again, going back to the question that you raised about the way that glycans can be viewed as a source of agents with therapeutic applications. So, in IBD, and that's what we identified and we also have evidences that if we change the glycosylation profile at the level of mucosa, this will consequently have an impact on the microbiota composition and this is something that we will explore in a deeper way, in this GlycanTrigger Project, which is actually a big consortium. We, University of Porto, will coordinate the consortium but we have many other partners across the globe, I would say.

Rina Bogdanovic [30:07] You have talked already about the potential of glycans as biomarkers, as well as therapeutic agents, but just thinking of perhaps patient stratification. How well do you think glycans could be potentially used as predictors of therapeutic response in patients with IBD as well as other autoimmune diseases?

Salomé Pinho [30:26] We also have some evidence on that. So, we show that the levels of glycosylation not only the levels but also the abundance and the composition of the of the mucosal glycome detected in a biopsy that is collected upon colonoscopy has prognostic value. So we show with that, for branched glycans and that was one of the glycan structure that we assess it and explore the potential prognostic value, we found that the levels of expression of branching glycans at the level of colonic mucosa in patients with the inaugural diagnosis of ulcerative colitis can predict the failure to standard therapy, and therefore, the eligibility to step up to more aggressive and powerful therapy, such as the case of biologics in case of IBD patients. So, these of course, I like the power of these glyco-biomarkers as important tools for, I mean, to be included, actually, in the clinical and therapeutic algorithm of IBD decision. So not only clinically but also therapeutically. So one thing that we will discuss, based on the evidence that we gather is that the way that the mucosa, colonic mucosa, is composed with glycans can inform the clinicians on whether to start early and aggressive immunotherapy would be better than to follow the step by step therapeutic intervention that starts in the classical anti-inflammatory agents and in a step up approach, I mean, increases the immunomodulatory power of the of the immunomodulation.

Rina Bogdanovic [32:15] I mean, especially thinking of it in terms of quality of life and just reducing the amount of pain these patients would have to go undergo before the right therapy is found, that's amazing to think about. But now trying to circle back to cancer, is there an increased risk for individuals with an autoimmune disease to develop cancer based on your work?

Salomé Pinho [32:37] And the other way around is also true. So, there is this fine, very tiny little line that separates tolerance and what happens in autoimmunity, what happens in cancer if we look to cancer as an immune suppressive environment. So, what happens in cancer and actually immunotherapy has revolutionized cancer therapy in the last couple of years. So essentially what we have in the cancer microenvironment is a, our networks with an immune suppressive, an immune regulatory response that actually allows cancer development and cancer progression, because there are strategies that are used by cancer cells to evade immune recognition and to contribute to the creation of these immunosuppressive networks. So, one of the strategies that are using that actually, I mean, transformed the therapy in cancer is actually the immunotherapy, which is actually to remove the brakes of these immune cells, specifically the T cells by inhibiting the immune checkpoint inhibitors, for example, PD-1 and CTLA-4, are strong immune checkpoint inhibitors, that suppresses the T cell mediated immune response. And immunotherapy, the aim is exactly to remove that brakes to potentiate an effective T cell mediated immune response. But of course, these might fall in this tiny little line and at the end will have an exacerbation and uncontrolled T cell mediated immune response that may result in autor reactive responses. And actually, there is not neglected proportion of patients and the immunotherapy with immune checkpoint inhibitors that cancer patients actually and immune checkpoint inhibitors that may develop an experience rheumatic and autoimmune diseases such as lupus, such as Crohn's disease, but the other way around is also true. So, what we want in these autoimmune responses and for example, IBD, but also lupus is the opposite. So, we have an uncontrolled immune response and exacerbation of the T cell mediated immune response and we need to suppress. And sometimes we are suppressing so much at such higher level, that these may create the space and condition, the spatial temporal conditions, for cells to transform, because the environment will become quite suppressive, regulatory, and cells take advantage and just transform leading to cancer episodes. The same holds true so autoimmune, the patients with autoimmune disease under this immune suppressive therapy may develop cancer.

Rina Bogdanovic [35:33] You've been mentioning the glycan switch quite a lot during this conversation. And I would like to just point to a recent ERC synergy grant, which you and three other PI's have been awarded, focusing on the glycan switch and B cells. Could you tell us a bit more about that?

Salomé Pinho [35:53] So the GlycanSwitch is a recent ERC synergy funded project. That's besides me as a PI, we also have more three PI's. So, Gordan Lauc is another PI, but also Manfred Wuhrer, and Tom Huizinga from the Leiden University Medical Centre are the other two PI's. So, it's all about glycans, of course, and the relevance in this process of tolerance. So, the GlycansSwitch also as GlycanTrigger funded by the European Commission. But of course, in this case, the European Research Council. And with GlycansSwitch, we aim to dissect whether the switch that we have evidence that occur at the level of B cells, and this occurs at the level of B cells preceding the development of autoimmune diseases such as rheumatoid arthritis. So, we want to understand when, why, and how this switch on the glycosylation profile of B cells occur, the mechanism behind that, and the way that we could prevent the switch, and at the end by preventing the glycan switch we could prevent the development of rheumatoid arthritis and intercept disease development.

Rina Bogdanovic [37:12] First of all, I want to congratulate you for both of these projects. It's very, very impressive. I want to mention for ERC, if I'm not mistaken, you are the third Portuguese scientist ever to be awarded this grant. So, it's an incredible accomplishment in your career!

Salomé Pinho [37:29] Thank you so much.

Rina Bogdanovic [37:30] If we could quickly just touch back on the glycan switches. You have a very interesting study looking at glycan switches in T cells in relation to COVID-19. And I think this is still a pretty current topic, sadly, three years later, but yeah, a little bit about that study.

Salomé Pinho [37:48] That was our contribution as glycoscientists, of course, to understand the disease. And so I mean, the reason for our contribution is because we, as scientists, we couldn't just stand by in the middle of a pandemic. And there was a national, in Portugal, a national and as in other countries, and the national initiative by our research funding agency, I mean, to promote research in the field, and for all of the scientists that would be interested, and we know how could contribute, of course, to understand the disease and the virus and the pandemic. And actually, we took advantage of our know how on glyco-immunology and specifically on T cells glycosylation. And we decided to essentially screen a cohort of COVID- 19 infected individuals, so SARS-CoV-2 infected individuals, and to see what happens to the circulating T cells in terms of the glycosylation profile. So, and making a long story short, what we observed was that infected individuals that develop a worse disease prognosis or developed a severe disease, in comparison with those patients with a mild disease have a different T cell glycosylation profile. So essentially, those patients that were able to switch quite efficiently, the glycosylation profile of T cells towards a completely different glycosylation signature, were more able to deal with the virus. And I mean, this was associated with a good prognosis with a good disease course, in comparison with the others that upon infection with SARS-CoV-2, the T cells maintained quite, I mean, inefficient in terms of the of the glycan switch, I mean, enabling the T cells to efficiently deal with the virus. So essentially, we found that upon infection with the virus, there is a glycan switch. And depending on the efficacy of the switch, this is associated with the prognosis of the disease. Yeah. And that's, that was our contribution to the field.

Rina Bogdanovic [39:59] Thank Salomé. I think we've definitely covered a lot of topics today, is there a final message you would like to share with our listeners?

Salomé Pinho [40:09] Thank you so much for the kind invitation and for these minutes of very nice conversation about glycans, which is something that I appreciate very much. Thank you.

 

Rina’s outro

Rina Bogdanovic [40:20] I hope this conversation helped you better appreciate the nuances of immune regulation and the bright future of glycan prognostic and diagnostic biomarkers. If you would like to access more information about this conversation and Salome’s previous work, follow the link in the description to the show notes for this episode. Equally, if you want to find out more about GlycanAge, head on to glycanage.com where you can access a whole list of our scientific publications, blog posts, testimonials and of course this is where you can order your GlycanAge kit. Watch out for our next episode where I will be joined by Olga Zaytseva, a geneticist focusing on genetic regulation of IgG glycosylation. We will discuss the genetic and epigenetic control of IgG glycosylation and by extension chronic inflammation, especially in the context of behaviour and lifestyle. Please don't forget to leave ratings and reviews for this episode and engage with us on social media. All the links will be in the description. Thank you for listening and have a great day.

 

 

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Please be advised that this show is for information only and should not be considered as a replacement or equal to medical advice.