The tumor microenvironment (TME) that surrounds solid cancers has long held fascination for researchers. Yet it is only relatively recently that we’ve understood how important the TME is for influencing progression of the disease and response to treatment. In this article we learn why it’s not just the tumor itself that needs to be targeted and hear about research that aims to exploit the TME, too.
The tumor microenvironment and immune response
In solid tumors, cancer cells are supported by the stroma – cells that support the tumor both physically and by producing growth factors. There are also blood vessels in the tumor (usually highly disorganized), which provide oxygen and food to the tumor, and carry immune cells. Whether these immune cells can penetrate the cancerous area is crucial in determining whether immunotherapy will work, and this is now a major focus of research into the TME.
At Cardiff University, Dr Zsuszanna Tabi is investigating whether different types of tumors have inflammatory or immunosuppressive environments.
“The biggest breakthrough in cancer treatment happened in the last decade or so with the success of melanoma treated with immune checkpoint inhibitors. About 20–30% of patients with advanced disease respond extremely well to this treatment, which “takes the brake off” the immune cells, with complete recoveries or long remissions often observed,” says Tabi. “But in the remaining 70–80% of patients the TME is either too "hostile” (i.e. immunosuppressive) to allow this immune treatment to work, or the right immune cells are simply not present. So, a major focus is to find out how the TME can be changed in order to enable the checkpoint inhibitors to work.”
Some cancers, such as prostate cancer tend to be immunologically “cold”, i.e. not much is happening, the immune system is not fighting the cancer, whereas melanoma is a “hot” tumor where immune responses are very important and these patients respond well to immunotherapy. Tabi is investigating whether these “hot” or “cold” immune phenotypes hold true in other cancers. She is particularly interested in mesothelioma, an aggressive form of lung cancer with poor survival rates.
“An inflammatory environment is advantageous while an immunosuppressive environment allows the tumor to progress,” she explained. “Mesothelioma is interesting because there are two types of mesothelioma: one is hot and the other is cold and there is nearly nothing in between. However, because there are not many immunotherapy trials in mesothelioma, we don’t really know the meaning of this yet.” she says.
“Then it gets even more complex because there are some multifocal tumors where each lump is different – so within one patient, one tumor could be immunologically cold and another hot. In this scenario, it has been observed that some of the lumps can be removed with successful immunotherapy but the others can’t.”
To test whether an anti-tumor immune response could be achieved in mesothelioma, Tabi initiated a clinical trial in mesothelioma where the patients were vaccinated with an attenuated virus that carried cancer antigens. The patients received it together with chemotherapy and they monitored the immune changes in the blood. Of the 23 patients taking part, 22 had a marked increase in their anti-tumor response1. This kind of treatment is now being tested in a combination with other, more targeted interventions. “Our trial was an important step in that direction because mesothelioma is such an aggressive disease and it’s nearly impossible to have a complete remission and the survival rate is very low.”
For the future, in addition to changing the immune profile to improve the effectiveness and general outcome of immunotherapy, Tabi also highlights another important player in the TME – cellular exosomes. These tiny particles are released by cells in order to communicate with each other.
“Exosomes are getting a lot of attention recently, as tumor cell-derived exosomes are important in changing the normal microenvironment to make it more receptive for the tumor to spread,” says Tabi. “Several years ago, there was an attempt to use exosomes as a cancer vaccine. We always thought that was a bad idea. Now we have the evidence to show that, yes, they carry tumor antigens, but it’s not possible to use them as a cancer vaccine because they have dominant immunosuppressive effects.”
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The immune status of the TME is also thought to be particularly important in the development of cancers caused by chronic inflammation. According to Dr Stuart McDonald from the Cancer Research UK Barts Centre at Queen Mary University of London, chronic inflammation cancers account for around 1 in 4 cancers and are associated with some of the poorest outlooks for patients. They include bowel cancers that tend to occur in people with inflammatory bowel disease or ulcerative colitis, and esophageal cancer that arises from the inflammatory condition Barrett’s esophagus.
McDonald is part of an international Grand Challenge team “STORMing Cancer” led by Prof Thea Tlsty (University of California San Francisco) and funded by Cancer Research UK looking at how the stroma microenvironment plays a role in inflammation-associated cancers. “We’ve always known that there’s an increased risk of cancer with chronic inflammation patients compared to the rest of the population, we just don’t know why,” said McDonald. “There’s evidence to suggest that stromal cells can actually promote or even transform epithelial cells into malignancy. But we know very little about the molecular pathways and the stromal pathways that are switched on, switched off, and how to treat them.”
Rather than look at the epithelium of these tumors and sequence them, the Grand Challenge team plans to focus on the cells that normally maintain these epithelial cells, to understand how these become distorted during inflammation and how signaling pathways between stromal cells, the extracellular matrix and the epithelium drive tumorigenesis. The team view inflammation-associated cancers as a disease process rather than individual cancer types.
“First, we need to characterize the stroma because it’s really not been done, so we’re probably missing lots of targets that we just don’t know about,” says McDonald. “Then we want to use that information to try and predict which patients are going to develop cancer and which ones aren’t.”
To achieve this goal, the international Grand Challenge team will combine a broad range of technologies. First, in a discovery phase, they plan to develop maps of these chronic inflammation cancers from understanding RNA and protein expression, immune environment and creating databases to help predict or determine targets. They’ll also exploit CODEX technology (provided by Professor Garry Nolan, Stanford)– which allows you to measure the expression of 60–100 targets on a cell section to investigate cell-cell neighborhoods, and understand, if one cell is present – how does it talk to the other cells around it?
In a subsequent development phase they will look at the targets identified from the -omics and CODEX analysis and build these into an in vitro model using organ-on-a-chip technology – a model that is far more tissue-like because you can model effects such as the peristaltic motion of the bowel and blood flow on a 3D chip (Professor Don Ingber, Harvard). This will be combined with in vivo models that allow them to interrogate the effects of targeting stromal factors on stem cell biology and tumorigenesis.
McDonald’s role is to take these data and apply it to patients. “We’ll use samples from patients we’ve collected over time, who have progressed to cancer, and try to identify which factors predict progression and which ones don’t,” he explains.
One of challenges from a clinical perspective with chronic inflammation cancers is that very few people with the inflammatory condition go on to develop cancer. “In Barrett’s esophagus, the progression rate per year is about 0.1–0.3% of all BO patients,” says McDonald, “yet every single person will go through a two- to five-year endoscopic surveillance program that is invasive, expensive and does not predict if they will develop cancer.”
“By looking at changes to the stroma over time, we’re trying to predict: how do these cell populations evolve? How do they talk to each other? Is the risk there when the patient develops the condition, and is it just a matter of time? Or is it something that changes at some point in the patient’s life? This would be an important advance in these types of cancers, because it helps with not only preventing cancers but also detecting the early-stage cancers that we sometimes miss.”
1. Lester J, Casbard AC, Al-Taei S et al. (2018). A single centre phase II trial to assess the immunological activity of TroVax® plus pemetrexed/cisplatin in patients with malignant pleural mesothelioma - the SKOPOS trial. Oncoimmunology, 7 (12): e1457597. DOI: https://doi.org/10.1080/2162402X.2018.1457597