Summary
For the last 4-5 years, Irene Ghobrial, MD, and researchers at Dana-Farber Cancer Institute, the Broad Institute of MIT and Harvard, and Massachusetts General Hospital have focused their efforts on trying to understand mechanisms of disease progression from early precursor conditions, like monoclonal gammopathy of unknown significance (MGUS), to myeloma. In defining what makes someone progress during their lifetime from MGUS to myeloma, the researchers hoped to be able to identify new ways to potentially prevent the progression and development of myeloma.
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Original Article
Immune System Changes Can Impact Development of Multiple Myeloma
Oncology Times
By Lindsey Nolen
For the last 4-5 years, Irene Ghobrial, MD, and researchers at Dana-Farber Cancer Institute, the Broad Institute of MIT and Harvard, and Massachusetts General Hospital have focused their efforts on trying to understand mechanisms of disease progression from early precursor conditions, like monoclonal gammopathy of unknown significance (MGUS), to myeloma. In defining what makes someone progress during their lifetime from MGUS to myeloma, the researchers hoped to be able to identify new ways to potentially prevent the progression and development of myeloma.
Before conducting the study, it was understood that multiple myeloma is preceded by precursor conditions like MGUS and smoldering multiple myeloma (SMM), in which people have abnormal plasma cells in their bone marrow but no physical symptoms or organ problems. However, not everyone with MGUS or SMM will go on to develop myeloma. To better identify individuals at risk and prevent the development of full-blown myeloma, the researchers envisioned finding new ways to intercede in the disease process early on.
Ghobrial, who came up with the idea for the overall study, organized the necessary collaboration and used her patients for an official bank of samples, explained that the study focused on two different areas of progression. The first was on the tumor cells themselves, including the genomic epigenetic ethical alterations that lead to disease prevention. The second was on immune and non-immune microenvironments, specifically regarding what happens in the bone marrow microenvironment that interfaces with the tumor cells and can lead to them being permissive, non-permissive, or allowing progression.
“For many years the immune system has been known for the ‘Three Es’: escape, elimination, and equilibrium,” Ghobrial said. “We wanted to understand what the interactions of the immune cells in the bone marrow with tumor cells were. The other thing that was important was that we knew some patients with MGUS or smoldering myeloma have the same genomic changes as cancer cells, but some of them may progress more rapidly than others do.”
She added that her team’s initial thoughts were that an immune dysregulation is what allows certain conditions to progress into myeloma more rapidly, and that it was not only genomic changes making this impact. Another thought was that maybe there were no genomic changes and progression was truly an immune escape. New technology allowed the researchers to use single-cell RNA sequencing to map changes in the immune microenvironment in myeloma precursor conditions. They were able to gather several samples of healthy individuals, those with MGUS, smoldering and myeloma.
“The nice thing about single-cell sequencing, as compared to bulk sequencing, is that it is like looking at a forest versus looking at a tree,” Ghobrial explained. “You can look at the forest in general and see major changes, but you cannot really define them at the tree level. Single-cell sequencing really takes each ‘tree’ on its own and defines it and understands better the composition, and that gives you a much higher resolution of what’s going on in that environment.”
Ghobrial explained that, through RNA single-cell sequencing, her team was able to define in a non-biased fashion all of the different cells that were present in the microenvironment. In collaboration with Gad Getz, PhD, who designed many interesting algorithms, they were able to better understand how cells act as the center of composition, how cells are the transcription of composition, and how they are different across the different states.
Their analysis revealed that, long before multiple myeloma becomes a malignant disease, the collection of immune system cells and signal carriers amid the tumor cells undergoes dramatic shifts. These shifts include the possible alteration of the number and type of immune cells. In fact, during myeloma development immune changes such as an increase in the number of natural killer (NK) cells, the loss in SMM of memory T cells and a dysregulation of certain monocytes can point to the progression of myeloma.
For example, patients with the highest volume of NK cells tended to see that the cells become a type that is drawn into the bone marrow in response to signaling molecules. The findings also suggested that treatments that replenish or activate memory T cells could be effective in some patients. Additionally, in myeloma precursor conditions, myeloma cells can prevent monocytes from being presented, resulting in a lesser immune attack on the cancer.
“This information helps define the landscape of early precursor conditions like MGUS and shows us that, even at an MGUS stage, the patient has an immune system that is not normal,” Ghobrial said. “This is important because we used to think that MGUS was benign, but actually it’s not that benign. Many patients do have an immune dysregulation, and that’s important to note.”
While the results are a step forward in the goal to achieve more personalized treatment of myeloma and precursors based on the immune microenvironment in patients’ bone marrow, there is still more work to be done. Yet, if the definition of increased biomarkers continues to point to the immune system as the cause of abnormal microenvironments, future treatments can begin to be geared more toward the immune microenvironment of each patient’s disease. This would include the specific constellation of immune cells in and around myeloma tissue.
“Next, we need to use a larger cohort of sequential samples of patients so we can monitor the same patients when they progress or when they do not progress,” Ghobrial said. “This is so that we can have better biomarkers for defining whether this happened before cancer cells evolved or after; which one came first. We must define whether they’re truly causative or not, meaning that there are still lots of questions to be answered.”
Lindsey Nolen is a contributing writer.