Researchers at the UC San Diego School of Medicine and Moores Cancer Center have identified a molecular switch that controls immune suppression, which could lead to refinements of emerging immunotherapies that boost the body’s own abilities to fight diseases ranging from cancer to Alzheimer’s and Crohn’s diseases.
The findings were published in Monday’s online issue of Nature.
“Immunotherapies, such as T cell checkpoint inhibitors, are showing great promise in early treatments and trials, but they are not universally effective,” said Judith Varner, a professor in the departments of Pathology and Medicine at the UCSD School of Medicine.
“We have identified a new method to boost the effectiveness of current immune therapy,” Varner said. “Our findings also improve our understanding of key mechanisms that control cancer immune suppression and could lead to the development of more effective immunotherapies.”
When confronted by pathogens, injury or disease, the initial response of the body’s immune system comes in the form of macrophages, a type of white blood cell that produce pro-inflammatory proteins called cytokines that, in turn, activate T cells, another immune cell, to attack the health threat.
The macrophages then switch gears to express other cytokines that dampen T cell activation, stimulating tissue repair.
In chronic inflammatory diseases such as Alzheimer’s and Crohn’s, however, macrophages continue to produce cytokines and other substances that kill or transform normal cells. In cancer, highly abundant microphages express anti-inflammatory cytokines that induce immune suppression, effectively stopping the healing process.
Varner and her colleagues pinpointed a suspected cause — an enzyme in macrophages called PI-3 kinase gamma. In mouse studies, they found that the enzyme promotes immune suppression by inhibiting activation of anti-tumor T cells.
Blocking PI3Ky activated the immune response and significantly suppressed growth of implanted tumors in animal models, the scientists said. It also boosted sensitivity of some tumors to existing anti-cancer drugs and worked with existing immune therapy to eradicate tumors.
Varner and colleagues at the Moores Cancer Center also found a molecular signature of immune suppression and response in mice and cancer patients that may be used to track the effectiveness of immunotherapy.
Researchers with Infinity Pharmaceuticals participated in the study, which was funded, in part, by the National Institutes of Health, the CAPES Foundation of Brazil, the Brazilian Ministry of Education, and Ralph and Fernanda Whitworth of Rancho Santa Fe.
—City News Service
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