Researchers at the Francis Crick Institute have uncovered a protein that aids tumors to evade the immune system and is a likely candidate as a new immunotherapy target. Their findings are published in the journal Cell in a paper titled, “Secreted gelsolin inhibits DNGR-1-dependent cross-presentation and cancer immunity.”
“Cross-presentation of antigens from dead tumor cells by type 1 conventional dendritic cells (cDC1s) is thought to underlie priming of anticancer CD8+ T cells. cDC1 express high levels of DNGR-1 (a.k.a. CLEC9A), a receptor that binds to F-actin exposed by dead cell debris and promotes cross-presentation of associated antigens. Here, we show that secreted gelsolin (sGSN), an extracellular protein, decreases DNGR-1 binding to F-actin and cross-presentation of dead cell-associated antigens by cDC1s,” the authors wrote.
The scientists identified secreted gelsolin, a protein that is present in blood plasma and is also secreted by cancer cells, and discovered how it interferes with the immune system’s defenses by blocking a receptor inside dendritic cells.
Clinical data and samples from cancer patients with 10 different types of the disease were analyzed, and the researchers observed 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.
The researchers also discovered that blocking the action of secreted gelsolin in mice with cancer increased their response to treatments including checkpoint inhibitors.
“The interaction between tumor cells, the surrounding environment, and the immune system is a complex picture,” explained Caetano Reis e Sousa, PhD, group leader of the immunobiology laboratory at the Crick and one of the study’s authors. “And although immunotherapies have revolutionized the way certain cancers are treated, there’s still a lot to understand about who is most likely to benefit.
“It’s exciting to find a previously unknown mechanism for how our body recognizes and tackles tumors. This opens new avenues for developing drugs that increase the number of patients with different types of cancer who might benefit from innovative immunotherapies.”
The researchers observed that secreted gelsolin 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, PhD, 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.”
“Our results reveal a natural barrier to cross-presentation of cancer antigens that dampens anti-tumor CD8+ T cell responses,” wrote the researchers.
The team is hopeful they can 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. Their findings may pave the way for other strategies and treatments that target this protein.