In our previous blog post (check it out here), we explored how the microbiota can have a profound impact on our body’s systemic immune response. Did you know the diversity and identity of your gut microbiome can affect responsiveness to (immune)therapy?
This raises an interesting question: can we use the types and numbers of the species living in your gut and the metabolites they produce to predict how well you will respond to certain therapies? In the context of cancer immunotherapy, studies have shown that the presence or absence of specific microbes can be associated with better anti-tumor T-cell responses following cancer therapy. Indeed, in a mouse model, anti-CTLA4 antibody treatment was effective in controlling tumor progression only in specific pathogen-free animals, not in germ-free animals (animals raised without microbes). But then, when they introduced again distinct Bacteroides species in these germ-free animals, the expected effects to the antibody treatment were restored. Similarly, anti-tumor effects were perceived by the introduction of species Bifidobacterium along with anti-PD1 antibody treatment against melanoma. Amazing right??
Well, currently the field of the microbiome at the intersection of immunotherapy is a very active field of research and some microbiome-targeted therapeutic strategies have been successfully implemented. For example, fecal microbiota transplantation from response donors has shown beneficial effects on intratumoral immune activity.
The microbes matter, but their metabolites they produce also have significant impacts on immune therapy responses. For instance, short-chain fatty acids (SCFAs) have been shown to have beneficial effects on tumor cells, with higher concentrations associated with longer-term responses and longer progression-free survival. Also other metabolites can affect immunotherapy responses both either shaping a tumor-suppressing microenvironment, such as bile acids, inosine, kynurenine or a tumor-supressing microenvironment such as polyamides, lipotheichoic acid and ketone.
Ongoing studies are using microbiomics and metagenomics sequencing, along with metabolomics techniques, to evaluate the potential of the microbiome as a biomarker of patients' responsiveness to immunotherapy. The gut microbiome and metabolome are becoming increasingly critical research targets in the context of cancer immunotherapy. Exciting times lie ahead!
How can intestinal microbiota and its metabolites influence immunotherapy?
If you are with me, you agree that understanding how particular gut bacteria can affect the immune system is crucial. The microbes can trigger the outcome of immune therapy, specifically immune checkpoint inhibitors. They do that by affecting the immune system in two ways: antigen-dependent and antigen-specific.
For the first mechanism, certain bacteria can indeed influence the differentiation of CD4 T-cells into subsets of different immune cells impacting the final immune response. But these bacteria can also send signals and activate innate immunity via dendritic cells or macrophages providing an extra level of immune support. There is this probiotic, Lactobacillus rhamnosus, that was shown to promote innate immune responses in combination with anti-PD1 antibody by activating dendritic cells. This highlights the potential for probiotics to support our immune system in various ways.
Second, you have certain bacterial species that can trigger cross-reactive anti-tumor responses. They “mimic” the tumor antigens (antigen mimicry) that are targeted by T-cells and thus can amplify T-cells enhancing the immune response to cancer cells. Which is exactly what we want! Cool, no? This is relevant in immunotherapy, where targeting neo-antigens that arise from mutations in tumor cells is critical for the success of treatment. The amplification of T-cells can now also happen because of the presence of these bacterial species: they have similar epitopes to those of the tumor antigens creating a cross-reactive anti-tumor response. This microbe-cancer cross-reactivity seems to be very relevant for identifying therapeutic strategies and improving patient outcomes.
Source | Increased microbial diversity and the presence of specific species are associated with your immune response against the tumor, either beneficial or detrimental. Antigen-dependent mechanisms (left): specific immune responses are induced by commensal bacteria; Antigen-specific mechanisms (right): these appear by the presence of a specific epitope expressed in a particular species, for e.g. Bifidobacterium breve, T-cells react to these epitopes and cross-react with a neo-antigen (similar antigen). Cross-reaction between commensal bacterial and tumor antigens appear to be relevant in immune checkpoint inhibitor therapy.
In the context of antibody-based therapeutics, three questions appear to be relevant: (1) Can the gut microbiome profile be a biomarker to differentiate responders from non-responders in antibody therapy? (2) How can AI aid in predicting drug-microbiome interactions? (3) Can antibody-based modulation of the intestinal microbiome mediate immune tolerance?
The gut microbiome as a predictive biomarker for immunotherapy responsiveness
Machine learning methods are popular, and yes also for microbiome-based predictions!
Microbiome data have been used for predicting responses to immunotherapy. In a recent meta-analysis study, 16S rRNA taxonomic variables and community diversity indexes were used to train and validate their machine-learning models. Hierarchical clustering analysis revealed a higher response rate among patients with increased abundances of the Firmicutes phylum, while lower response rates for patients with increased abundances of the Bacteroidetes phylum. The ML models developed by the researchers to predict immunotherapy response status using microbiome features showed an AUC of 0.75, indicating good predictive performance and more interestingly, they showed cross-sequencing platform applicability suggesting the results are generalisable to broader datasets. Nice study, I find!
Of course, there is still plenty more research going on regarding ML models to unlock the microbiota’s potential to boost immunotherapy. However, this is not without any challenges. Microbiome datasets typically have this high dimensionality with relatively low sample sizes which leads to the common statistical problem the curse of dimensionality. Indeed, we have a very large P (number of ASVs, i.e. taxonomic features that make up the columns of your dataset combined with other relevant metadata) and a small N (number of samples). Luckily there are some tricks to deal with this cacophony of data, there are (many!) ways to calculate diversity measures by calculating the number of ASVs in a given sample (i.e. a person’s gut microbiome) summarizing these feature columns into 1 single column (known as alpha-diversity). You can also calculate beta-diversity to numerically describe and compare the diversity of the gut microbiomes between patients. A recent deep representation learning framework called DeepMicro uses autoencoders to compress microbial features. The embeddings were then used to predict various disease outcomes and were shown to accelerate model training process and improved the model performance on disease prediction task.
To accurately predict immunotherapy response, a patient's microbiota profile ideally should be combined with other predictive markers such as tumor mutation load, geographical factors, tumor type, and dietary variables. Therefore, researchers aim to integrate multi-omics levels in a multilevel and multidimensional research design towards personalized antibody therapy in the future. Despite challenges, the potential benefits of using machine learning to predict immunotherapy response based on gut microbiome data make it an exciting area of ongoing research.
Restoration of the gut microbiome: the intersection of antibodies and the microbiome
Maybe you are already convinced that the microbiome might be a game-changing breakthrough in revolutionizing immunotherapy treatments? For those who aren't … let’s dive in a bit deeper!
Did you know that there are clinical trials underway to evaluate the combination of microbiome therapeutics and immunotherapy, opening up exciting new possibilities for cancer treatment? One such trial is exploring the use of Bifidobacterium species in combination with pembrolizumab, an anti-PD1 antibody, for patients with advanced metastatic colorectal carcinoma, triple-negative breast cancer, and checkpoint inhibitor relapsed tumors. The combination therapy has the goal to target bacteria and bring beneficial immunomodulatory activity. The implications of this microbiome-immune research are enormous, and the possibilities are endless. By manipulating the microbiome, we may be able to unlock the secrets of the immune system and revolutionize cancer treatment. So stay tuned, because the future of cancer treatment is now, and the microbiome might take the lead.
… But what can the microbiome bring to improve antibody discovery?
Well, first we can take into account microbiome features because bacteria might affect the reactivity of T-cells. Recent research has shed light on this molecular mimicry that we touched upon in the beginning of this blog. It occurs between the microbiota and the antigens that T-cells react to. A study analyzing epitopes from 38 antigenic categories found that the sequence similarity of various antigens to the microbiota can either decrease or increase T-cell reactivity. The genus from which the microbiota homologous sequences were derived from could even determine whether a tolerogenic or inflammatory effect was observed. This research suggests that the presence or absence of microbiome sequences can contribute to the toleration or reactivity of T-cells. Yet another study showed that some bacterial peptides could modulate the immune response in human PBMCs in vitro, related to higher Th17 and Th22 responses. Yes, indeed, bacterial peptides seem to be inductors of human immune responses! wow!
As mentioned before, the repertoire of bacterial species in the gut might show potential similarities with tumor antigens. And they might be presented to immune cells as well! This goes together with co-signals that allow functional responses or maturation of subset of cells. So, it makes sense to identify bacterial components that share similarities with human tumor antigens because your immune system has already “seen” these antigens earlier (I hope you do remember this from the first blog!?). You might have built already an immune response against the microbiota sequence variant where then these immune cells will be reactivated by encountering the human tumor-related antigenic epitope. Thus, this re-encountering strengthens the anti-tumoral response and increases therapeutic efficacy. For the first time, a recent study showed high homology between peptides derived from microbiota species of the Firmicutes and Bacteroidetes phyla and tumor-associated antigens. The study suggests the anti-microbiota T-cell memory might turn out an anti-cancer T-cell memory that controls cancer growth when the expressed tumor-associated antigen is similar to the microbiota epitope. Indeed, it looks like that by maintaining a diverse gut ecosystem, cancer patients might have a selective advantage.
By the way, to be clear, keeping your microbiome as diverse as possible is always a good idea! By having a fiber-fueled diverse dietary pattern and a healthy lifestyle you literally feed your friendly microbes and I promise, you will thank them later! They are your friends, not your enemies …
But if your microbiome is not in balance, meaning there are more unfriendly microbes than friendly ones, the question is: can we selectively target those??
Well, though research is still in its infancy, it turns out that we can selectively enhance or deplete certain bacteria to increase responsiveness to therapy. The potential is incredible - imagine being able to specifically target pathogenic bacteria while leaving beneficial bacteria intact, or replacing gut antibodies in immune-deficient patients suffering from dysbiosis. Recent research has shown that antibodies produced by mice are uniquely specific to the bacterial species that reside within their gut microbiomes. Incredibly, these antibodies can be orally administered to immune-deficient mice, survive the trip through the stomach and intestines, and be found intact in fecal samples. This offers a potential new delivery route for therapeutic antibodies to target pathogenic bacteria, without the need for invasive procedures or systemic antibiotics.
This breakthrough research offers hope for a future where microbiome therapeutics could be used to restore immune tolerance and selectively alter bacterial colonization. By targeting specific bacteria, we could increase therapy responsiveness in patients. Plus, the use of oral antibodies is associated with hardly any side effects, making it a promising alternative to current antibiotic therapies!
Conclusion
You understand now (well I hope you do?) that the microbiome is a complex ecosystem that plays a crucial role in maintaining our health and well-being. We can even manipulate our microbiome ourselves to have these beneficial effects on our immune system and in case of illness, they even can improve disease outcome. Incorporating microbiome features into immunotherapy development is thus a promising approach that may enhance its effectiveness. Various clinical trials are underway that evaluate the combination of microbiome-therapeutics and immunotherapy such as fecal microbiota transplantation, live biotherapeutic products, or pro/prebiotics supplementation. The recent discovery of specific antibodies that can target pathogenic bacteria while leaving beneficial bacteria intact opens up new avenues for therapeutic development that may replace antibiotics in the treatment of dysbiosis and immune-deficient patients.
As we continue to unravel the mysteries of the immune system along, we may discover even more innovative approaches to treating diseases and improving overall immune health. But one thing is clear: protecting and nurturing our microbial friends could be the key to unlocking a new era of cancer treatment.
So the next time you reach for that antibiotic, remember that the key to optimal health is a healthy, diverse microbiome - and it starts with you!
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