How does the immune system recognise and destroy Hodgkin lymphoma?
In Hodgkin lymphoma, the cells which are the root cause of the cancer are hidden within a much larger number of white blood cells. These white blood cells are usually very good at killing cancer cells, but may be unable to kill all of the Hodgkin lymphoma cells. Bloodwise Visiting Fellow Dr Zumla Cader has been investigating why...
When the body makes a new cell, it’s very easy for errors to happen as the DNA is copied from the existing cell to a new cell. These errors aren’t necessarily bad, since some don’t have any effect on the body, but some can cause the cell to become cancerous. Our immune system contains white blood cells, which can detect harmful invaders like bacteria and viruses, as well as find and kill cancer cells. One type of white blood cell called a T cell can identify and destroy cells which “look different” and are potentially harmful. Another type of white blood cell called a macrophage works together with T cells to eat the debris left from the destroyed cell.
However, T cells are very powerful killing machines, so they have to be stopped from attacking healthy cells after they’ve done their job. Luckily, there is an ‘off switch’ on the T cell, a protein called PD-1. Once a T cell is activated PD-1 is expressed on the its cell surface, which triggers the T cell to switch off when it comes into contact with another protein, PD-L1, on the surface of the macrophage.
Hodgkin lymphoma and the T cell off-switch
Imagine you are a cancer cell. You want to keep yourself alive, but T cells are trying to kill you. There are several ways you might defend yourself: hiding, making lots more cells so that there are too many of you for the T cells to destroy, or stopping T cells from working properly.
A T cell, seen under a scanning electron microscope (SEM). SEMs work by bouncing tiny particles called electrons off the surface of a cell, meaning that researchers can see the cell in very high detail.
Hodgkin lymphoma cells are good at hiding from T cells and making sure T cells do not work properly. The cancer cells have PD-L1 proteins on their surface so any T cell that comes into contact with them will switch off instead of destroying the cancer.
Fortunately, there are drugs available – including one called nivolumab – that can block the PD-1 proteins on T cells. This means T cells cannot be turned off by PD-L1 proteins, keeping them activated and free to destroy cancer cells.
But the T cells then face another challenge: the cancer cells need to be recognised as something “different” to be destroyed. Every cell in our bodies is identified as belonging to us by a group of proteins called MHCs found on the surface of the cell. T cells constantly survey the body for cells that do not have the right MHC proteins and should be destroyed.
MHC proteins come in two types, class I and class II. In many cancers, it’s likely that the MHC class I proteins are what allows the immune system to recognise and kill cancer cells. However, MHC class I proteins are often missing from Hodgkin lymphoma cells, so Dr Zumla Cader and her collaborators around the world have been investigating MHC class II proteins, which are found on Hodgkin lymphoma cells. The results were published in the Journal of Clinical Oncology.
Targeting Hodgkin lymphoma cells
The researchers were interested in understanding what role MHC class II proteins play in whether T cells destroy Hodgkin lymphoma cells. To find out, they used samples given by people with relapsed or treatment-resistant Hodgkin lymphoma who had taken part in a clinical trial testing nivolumab. They looked at each sample for levels of MHC class I and MHC class II, as well as PD-L1, the defence protein on Hodgkin lymphoma cells that causes T cells to stop working. They also noted how many people were no longer showing signs of cancer after treatment (“complete response”) and how long after treatment each person lives with the disease without it getting worse (“progression-free survival”).
All Hodgkin lymphoma cells from people taking part in the trial had high levels of PD-L1, but those with the highest level showed the most benefit from nivolumab’s PD-1 blocking effect. Many had also lost MHC class I proteins, as is often the case in Hodgkin lymphoma. Importantly, almost all the people who had a complete response to treatment had MHC class II proteins on their Hodgkin lymphoma cells. Everyone who had taken part in the study had undergone a stem cell transplant, which wipes the existing immune system with the intention of rebuilding a healthy, cancer-free immune system. However, this rebuilding is a long process and it can take many months before T cells are again fully functional. In people with fully rebuilt immune systems, intact MHC class II proteins were associated with longer progression-free survival.
A stem cell transplant wipes the existing immune system so that there is a 'blank slate' for a new cancer-free immune system
Since most people who had a complete response to treatment did not have any MHC class I receptors on their Hodgkin lymphoma cells, it is likely that T cells destroy these cells using a different mechanism to that described in other cancers. Dr Cader and her colleagues theorize that the T cells that recognise MHC class II proteins may have a more important role than T cells that recognise MHC class I proteins in determining how well people with Hodgkin lymphoma will respond to treatments like nivolumab.
I asked Dr Cader what her findings could mean for people with Hodgkin lymphoma. “Thankfully, most patients with Hodgkin lymphoma respond well to treatment and are cured but a small number do not respond despite our best efforts,” she said. “PD-1 blockade with drugs like nivolumab works very well, but this research allows us to identify those who are likely to get the greatest benefit and start to identify ways to improve treatment options for those who do not respond well.”
The team are now working on understanding how the immune cells respond to Hodgkin lymphoma cells, and have recently published a second journal article in Blood with findings that indicate that there are lots of T cells around Hodgkin lymphoma cells. Unfortunately, these T cells are either ‘exhausted’ and cannot destroy the Hodgkin lymphoma cells, or they are a kind of T cell that ‘turns down’ the effectiveness of other immune cells. This research is still in its early stages, so at the moment the researchers are looking to deepen their understanding.
This research might also be useful for people with other types of cancer. Dr Cader says, “We have shown that a specific type of T cell which recognises MHC class II is likely to have an important role in killing cancer, which we didn’t know before. Other cancers also have decreased MHC class I to hide from the immune system so T cells with a receptor called ‘CD4+’ on their surface, which isn’t affected by this loss of MHC class I, may have a previously unappreciated role in those cancers too.”
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