The balancing act that is cancer immunotherapy requires that the body’s antitumor response be given a boost, but not too much of a boost. For example, simply getting rid of Tregs, the regulatory T cells that moderate the immune system’s attack on cancer, would be risky. Such a rash act might precipitate a dangerous autoimmune reaction. An alternative, less extreme approach would be to inhibit Tregs while keeping them around.
Merely tinkering with Tregs, Columbia University researchers suspected, could boost cancer immunotherapy without letting the immune system get out of control. When the researchers tested the idea, by using a drug that interferes with Treg transcription, they found that standard checkpoint-blockade immunotherapies became more effective in mouse models.
Details of this work appeared September 7 in the journal Cell, in an article entitled, “NF-κB c-Rel Is Crucial for the Regulatory T Cell Immune Checkpoint in Cancer.” In this article, the Columbia University scientists report that NF-κB c-Rel ablation specifically impairs the generation and maintenance of the activated Treg (aTreg) subset, which is known to be enriched at sites of tumors.
“Using mouse models, we demonstrate that melanoma growth is drastically reduced in mice lacking c-Rel, but not p65, in Tregs,” the article’s authors wrote. “Moreover, chemical inhibition of c-Rel function delayed melanoma growth by impairing aTreg-mediated immunosuppression and potentiated the effects of anti-PD-1 immunotherapy.”
In mice with melanoma, the researchers found that the drug—called pentoxifylline—boosts the effectiveness of immune-checkpoint inhibitors, a type of immunotherapy now commonly used in the treatment of melanoma and other cancers. Pentoxifylline, the current study suggests, may be able to improve the odds that immunotherapy will be effective in cancer patients.
Checkpoint-blockade immunotherapy drugs—the first drugs were approved in 2011—target proteins on tumor cells or cells of the immune system that prevent “killer” T cells from attacking cancer. These drugs have revolutionized cancer care, but do not work for all patients.
“In advanced melanoma, for example, the cure rate is only about 20%. That's a remarkable improvement over previous therapies,” said study leader Sankar Ghosh, Ph.D., a professor of microbiology and immunology at Columbia University Medical Center. “But why doesn't it work for the other 80 percent? There must be another mechanism that contributes to the suppression of the immune response.”
Dr. Ghosh and colleagues decided to try weakening, but not abrogating, the Treg mechanism. Large numbers of these Tregss are found within several types of tumors. “One possible therapy would be to get rid of Tregs,” explained Dr. Ghosh. “But Tregs are also needed to keep the immune system in check, and shutting down Tregs completely would unleash an attack against the body's healthy cells and organs.”
This point is underscored by a related study, published today in Immunity, in which Dr. Ghosh and colleagues found that removing NF-B from Tregs caused widespread and lethal autoimmunity in mice. However, a partial inhibition of NF-κB, achieved by removing only one, specific, NF-B protein, called c-Rel, changed Treg function without causing widespread autoimmunity.
In the Cell study, Dr. Ghosh and colleagues showed that these c-Rel-deficient Tregs were specifically crippled in their ability to protect cancer cells. As a result, when c-Rel is blocked, killer T cells mounted a more robust attack on cancer cells without causing autoimmunity.
Pentoxifylline is a drug that is used in patients to increase blood flow in the hands and feet of people with poor circulation, but it's also known to inhibit the c-Rel protein. In the Cell study, pentoxifylline blocked Treg function and boosted the effectiveness of standard checkpoint-blockade immunotherapies. As a result, mice treated with both drugs showed significantly reduced melanoma tumor burden, compared to animals that received the standard therapy alone.
“The next step is to test this drug combination in human clinical trials,” Dr. Ghosh noted. “If trials are successful, the use of c-Rel inhibitors could become a standard addition to immune checkpoint therapy for many types of cancer.”