Cancer immunotherapy is the latest treatment option in our fight against a debilitating disease. Although promising, it has a varied response rate. Recent research has shown that the success of cancer immunotherapy is associated with the gut microbiome1–4. From mouse models to cancer patients, insight into the importance of our gut microbiome comes from advances in metagenomic sequencing technologies.
Cancer immunotherapy targets the immune system of a patient and enables it to better fight the growing tumors in the body. Currently, the most common cancer immunotherapy focuses on a protein called PD-1 or Programmed Cell Death-1. This is a protein present on the surface of activated immune cells such as monocytes, natural killer cells, dendritic cells, B cells, and T cells1. The binding of PD-1 to its ligand PD-L1 helps our immune system to distinguish between self and foreign cells. This is so that our immune system would not attack our own body cells and cause dysregulation which happens in autoimmune disorders. However, in the case of cancer, since the tumor grows from our body cells, the immune system recognizes it as self and does not attack it. To get around this dilemma, a new class of drugs have been introduced which are PD-1 inhibitors. By blocking the binding of PD-1 to its ligand PD-L1, these drugs allow for the activation of the immune system which is then able to attack the tumor and shrink it. The U.S. Food and Drug Administration (FDA) has approved anti-PD-1 immunotherapy for at least 11 types of cancers1.
Role of Gut Microbiome in Cancer Immunotherapy
One of the most notable problems in using cancer immunotherapy is its unpredictable response. The number of patients who benefit from anti-PD-1 immunotherapy can range anywhere between 5-55%1. This means that almost half of the patients who have to suffer critical adverse events from this treatment derive no benefit from it. This added with the high treatment cost has urged researchers to explore biomarkers that can help to predict the treatment response in patients and identify those who would benefit from it. In this effort, one factor that has been intensely researched is the gut microbiome. For several different types of cancers, it is observed that responders to cancer immunotherapy have features of the gut microbiome that are distinguishable from non-responders1-4. These include hepatocellular carcinoma, melanoma, non-small cell lung cancer, renal cell carcinoma, and urothelial carcinoma. Responders to cancer immunotherapy carry higher microbial diversity that differs significantly in its composition when compared to non-responders. So, how can the gut microbiome affect our response to cancer immunotherapy? It turns out that a greater diversity and high abundance of microbial species alters our innate and adaptive immune system making them more vigilant and responsive towards anti-PD-1 therapy.
Our Gut Microbiome
There are more foreign cells in our body than our very own cells2. These are microorganisms ranging from viruses, bacteria, fungi, archaea, and protists. In fact, almost every nook and cranny of our body is home to these microbes, be it the skin, saliva, lungs, or uterus. The majority of these happen to reside in the gut and constitute the gut microbiome. So, from where and when did these microbes enter our body, or are we born with them? No, we are not born with them. In the first few years after birth, the body is exposed to a plethora of microbes in its environment. Some of these are better tolerated by the body than others and these end up becoming our lifelong lodgers.
Metagenomic Sequencing Technology
It is because of advances in metagenomic sequencing technology that the impact of the gut microbiome could be discovered in cancer immunotherapy. Until a few years ago, if researchers wanted to study the microbiome, they had to painstakingly collect samples from the body and try and grow each individual species in the lab in order to identify them. This was a momentous task that was made even more difficult by the fact that the majority of these microbial species refused to grow outside the body. This changed with the advent of metagenomic sequencing technology. Now a sample can be directly probed for all its constituent microbes without the need to first grow them painstakingly in the lab.
Targeted Amplicon Metagenomic Sequencing
To explore the effect of the gut microbiome on cancer immunotherapy, researchers compared the gut microbiome of responders versus non-responders through fecal samples. For this, they used targeted amplicon metagenomic sequencing. Here, the samples are probed for common genomic markers such as 16S rRNA for bacteria and 18S rRNA/ITS for fungi. These biomarkers are amplified by PCR and analyzed using the next-generation sequencing technology. When the data emerging from this is compared with microbial databases, it provides information about the identification, classification, and quantitation of microbes in your sample.
Shotgun Metagenomic Sequencing
An alternative to targeted metagenomic sequencing is when a sample is probed for all the microbial genetic material present in it. This refers to shotgun metagenomic sequencing and is especially useful to identify and characterize novel microbial species.
A pioneer in metagenomic sequencing, Novogene provides a range of services to explore the rich genetic repertoire of microbial communities. From advanced sequencing platforms to bioinformatics expertise, Novogene can assist you in every step of your research from exploring the species, to characterizing genes and biological pathways in your microbial communities.
Metagenomic sequencing technology has become useful in several areas of research. Our recent insight into the influence of the gut microbiome in cancer immunotherapy is just the latest in this series. Moving from the identification of the therapeutic species that are present in responders, to probing their metabolic pathways and characterizing their potential bioactivities—we have come to a step closer to modifying the microbiome for better cancer treatment. In fact, when researchers used germ-free mice for fecal transplantation—those mice who received fecal transplantation from responders were more sensitive to anti-PD-1 treatment in comparison to those receiving fecal transplantation from non-responders2. This means, in addition to monitoring disease and deciding treatment—metagenomic sequencing can assist patients to gain the most benefit from cancer immunotherapy.
1. Aghajani, M. J. et al. Pembrolizumab for anaplastic thyroid cancer: a case study. Cancer Immunology, Immunotherapy 68, 1921–1934 (2019).
2. Jin, Y. et al. The Diversity of Gut Microbiome is Associated With Favorable Responses to Anti–Programmed Death 1 Immunotherapy in Chinese Patients With NSCLC. Journal of Thoracic Oncology 14, 1378–1389 (2019).
3. Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018).
4. Zheng, Y. et al. Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma. Journal for ImmunoTherapy of Cancer 7, (2019).
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