In recent years there has been an increase in cancer treatments that target the immune system. So far, these therapies have not been effective in treating osteosarcoma (OS). Researchers are now trying to understand why these treatments are not working.
A recent study looked at the OS tumour microenvironment at a single cell level. This means looking at the individual cells that surround the tumour. This includes immune cells. The aim of the study was to provide insight into the immune landscape of OS and potentially shed some light on how it could be targeted by drugs.
The team analysed OS RNA sequencing data from previously published records. RNA sequencing is a technique that tells us which genes are turned on or off in cells. Doing this at a single cell level (instead of the entire tumour) allows us to know what is happening in each cell. This is important because tumours are complex and made up of many different cell types. A “map” can be created from the RNA sequencing data, where each cell is placed based on which genes are turned on in that cell. The cell type can be identified based on which genes were found. Cells that have similar genes turned on will be close to each other on the map. On this map, the researchers found several different immune cell types in the tumour microenvironment.
Dendritic cells are a type of immune cell that ‘patrol’ the body for things that should not be there. They ‘pick up’ bits of foreign substances called antigens and show them to other immune cells to activate an immune response. This could be against an infectious agent (e.g. virus, bacteria, fungus) or cancer cell.
There are several types of dendritic cells. Through analysing the RNA sequencing data the researchers found a subset of dendritic cells, called mregDCs, that were more common in the OS tumour microenvironment than in the surrounding tissue. The researchers then investigated what they were doing. They found that the dendritic cells may be recruiting regulatory T cells (Tregs) to the tumour microenvironment. Tregs suppress the immune system. This creates an environment where tumours can grow more easily. Although more research into how the mregDCs behave is needed, this initial study suggests that may have a role of bringing other immunosuppressive cells into the tumour microenvironment.
Cells with MHC class I
MHC class I molecules are another part of the immune system. They are found on the surface of most cells in the body. They can present antigens to other immune cells, activating an immune response.
This study found that levels of MHC class I were reduced in high-grade OS cells. This was seen both in the RNA sequencing data and when they looked at OS tumour samples. It is possible that a reduction in MHC class I could help OS cells evade the immune response.
Macrophages are immune cells that have several roles in the body. They clean up dead cells, stimulate other immune cells and they can ‘eat’ things that shouldn’t be there including cancer cells.
Macrophages are commonly seen in the OS tumour microenvironment. However, in OS macrophages do not always eat cancer cells and some subsets of macrophages may even be involved in helping the OS cells evade the immune system.
This study investigated why macrophages may not ‘eat’ OS cells. The researchers looked specifically at CD24, a marker found on the surface of cells, that is known to send ‘don’t eat me’ signals to macrophages. The data analysis showed that CD24 was frequently ‘turned on’ in OS cells compared with surrounding cells. The researchers investigated the role of CD24 in OS. Firstly, they analysed the effects CD24 had on OS cell lines (cells that are grown in a laboratory). They found that when the expression of CD24 was reduced the macrophages were more active. They then looked to see if they had the same response in mouse models. When CD24 was reduced in these models the tumours did not grow as quickly. Looking at the tumours more closely they also found that reducing CD24 in the mouse models increased the number and activity of immune cells at the site of the tumour. This included macrophages. These results suggest that OS cells can avoid macrophages through CD24 signalling. Therefore, blocking CD24 could increase the chance of macrophages destroying cancer cells.
All these findings are the first steps in the research process. They provide an initial springboard to explore the OS immune environment further. We hope to see more studies that focus on understanding how OS evades the immune system. From there we can find new drug targets and develop new treatments