Disguised Protein May Be A New Target For Cancer Immunotherapy
A crucial part of the immune system's response to cancer is a group of white blood cells, called CD8+ T-cells, which kill tumor cells. Before they launch their anti-tumor response, these cells must be told who to attack by another immune cell, called a dendritic cell.
In their study, published in Cell today (2 June), the scientists identified a protein that is present in blood plasma and is also secreted by cancer cells, secreted gelsolin, which interferes with this relay process by blocking a receptor inside dendritic cells. With no instruction passed to the T-cells, the tumors avoid their killer response.
The team analyzed clinical data and samples from cancer patients with 10 different types of the disease and found that individuals with liver, head and neck and stomach cancers, who have lower levels of this protein in their tumors had higher chances of survival.
They also found that blocking the action of this protein in mice with cancer increased their response to treatments including checkpoint inhibitors, a major immunotherapy.
This work builds on the team's research into dendritic cell biology. These cells absorb debris from dead cancer cells and hold them internally in pockets called phagosomes. Binding to a protein on the debris, F-actin, triggers these pockets to burst, releasing the debris into the cell where they can be processed and moved to the surface to signal the presence of a tumor to nearby T-cells.
When the researchers examined the activity of secreted gelsolin, they found the protein outcompetes a key dendritic cell receptor, blocking its ability to bind to F-actin and therefore the ability of the dendritic cells to initiate a T-cell response.
"Dendritic cells play a vital role in the immune system and our body's response to cancer," says Evangelos Giampazolias, author and postdoc in the Immunobiology Laboratory at the Crick. "Understanding this process in more detail will enable us to identify how cancers are able to hide and how we might remove their disguise."
"Reducing levels of this protein will help alleviate the competition for binding to F-actin and allow dendritic cells to communicate their vital message."
The researchers will continue this work, trying to develop a potential therapy that targets the secreted gelsolin in the tumor without affecting the activity of this protein in other parts of the body.
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