Dendritic cells are the sentinels of the immune system and use their “tree-like” projections to present antigens from pathogens to initiate the adaptive immune response. During cancer, dendritic cells are suppressed by chemical factors around the periphery of tumors, allowing these masses to grow and spread. On top of that, a subset of dendritic cells that are known to suppress the immune system is often recruited to the tumor site, limiting the ability of other immune cells to infiltrate and stall tumor growth.
Can we interrupt the tumor’s ability to evade the immune system? This is a question driving research at Mount Sinai, where scientists recently uncovered a molecular pathway that cancers use to block the infiltration and activities of dendritic cells. The team, led by Miriam Merad, Director of Mount Sinai’s Precision Immunology Institute also identified ways to leverage this pathway to boost cancer immunotherapy. The study was published in Nature.
The team used single-cell sequencing and state-of-the-art microscopy techniques to study human lung tumors as well as a mouse lung cancer model. They were particularly interested in the complex dynamics of dendritic cells and cancer cells at the interface of tumors and the healthy surrounding tissues. These interactions involved the interplay between multiple immune cells, particularly affecting the ability of T cells to destroy cancer cells. Cytotoxic lymphocytes, mainly cytotoxic T cells and natural killer cells have the ability to eradicate tumors. But first, they have to “see” them, with the help of dendritic cells. Merad and team identified chemical signals and molecular interactions involved in the breakdown of communication between dendritic cells and T cells at the tumor site.
These findings shed light on a contributing factor to why so many patients fail to respond to immunotherapies, a form of treatment that boosts the body's natural defenses against cancer. Currently, only about 20 percent of patients show signs of improvement following a form of immunotherapy called checkpoint blockades. By combining existing therapies with a second pharmaceutical intervention that overrides the suppression of dendritic cell activity at the tumor site, researchers are optimistic that this will drastically improve patient outcomes. A clinical trial to test this approach is being designed, in collaboration with biotech company, Regeneron.
"This study highlights the power of single-cell technologies to identify new therapeutic targets in cancer," says Merad.