Northwestern Medicine scientists have identified a novel strategy that could improve the efficacy of immunotherapy in treating chronic viral infections.
Immune cells called T-cells are critical for controlling tumors and viruses. But during chronic viral infection — such as HIV and hepatitis C — T-cells eventually become exhausted.
Immunotherapy, which strengthens the body’s own immune system to fight diseases, has become increasingly important in the area of cancer treatment. In a form called immune checkpoint inhibitors, antibodies target proteins that act as “brakes” on T-cells, such as PD-1. Once PD-1 is blocked, the T-cells are freed to launch an immune attack.
But although PD-1 therapies are now used to treat certain types of cancer — and the upregulation of immune checkpoints like PD-1 is a hallmark of T-cell exhaustion — the therapies have so far shown limited benefit in treating chronic viral infections.
Recently, research has suggested that the microbiome can influence the efficiency of PD-1 therapies; it was unknown, however, which specific microbial products might be beneficial.
In the current study, the scientists evaluated whether lipopolysaccharide (LPS) — a molecule on the surface of gram-negative bacteria — might affect response to PD-1 therapy in an animal model of chronic viral infection.
The team discovered that low doses of bacterial LPS in mice triggered an immune pathway called TLR4, which when combined with PD-1 therapy, revitalized the exhausted T-cells.
“This combined therapy resulted in a striking enhancement of immune responses to the virus — significantly greater than PD-1 therapy alone,” Penaloza said. “Our study demonstrates that immune checkpoint therapy can be substantially improved by just adding one specific microbial molecule.”
The authors caution, however, that much more research is needed in this area, and it is not yet clear if these results could be safely translated to humans.
In ongoing research, Penaloza’s laboratory is investigating whether the combinatory treatment might also be beneficial in models of cancer, as PD-1 therapy is currently only effective in a limited percentage of cancer cases.
Penaloza is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Other Northwestern authors include graduate students Yidan Wang and Young Rock Chung.
The study was funded by a grant from the National Institutes of Health (1R21AI132848-01A1).