By recruiting the immune system to fight tumor cells, immunotherapy has improved survival rates and offered hope to millions of cancer patients. However, only one in five people respond favorably to these treatments.
Seeking to understand and address the limitations of immunotherapy, researchers at Washington University School of Medicine in St. Louis have discovered that the immune system may be its own worst enemy in the fight against cancer. In a new study in mice, a subset of immune cells — type 1 regulatory T cells, or Tr1 cells — performed their normal function of preventing the immune system from overreacting, but did so while inadvertently restricting the cancer-fighting power of immunotherapy.
“Tr1 cells have been found to be a previously unknown obstacle to the effectiveness of cancer immunotherapy,” said senior author Robert D. Schreiber, PhD, the Andrew M. and Jane M. Bursky Distinguished Professor in the Department of Pathology and Immunology and director of the Bursky Center for Human Immunology and Immunotherapy at Washington University School of Medicine. “By eliminating or bypassing this barrier in mice, we have successfully reinvigorated cancer-fighting immune cells and uncovered an opportunity to expand the benefits of immunotherapy to more cancer patients.”
The study is available at Nature.
Cancer vaccines represent a new approach to personalizing cancer immunotherapy. Targeting specific mutant proteins in a patient’s tumor, these vaccines induce killer T cells to attack tumor cells without harming healthy cells. Schreiber’s group previously showed that the most effective vaccines also activate helper T cells, another type of immune cell, which recruit and expand more killer T cells to destroy tumors. But when they tried adding larger amounts of the helper T cell to boost the vaccine, they found that they generated a different type of T cell that inhibited tumor rejection rather than promoting it.
“We tested the hypothesis that by increasing the activation of helper T cells we would induce greater clearance of sarcoma tumors in mice,” said first author Dr. Hussein Sultan, professor of pathology and immunology. So he injected groups of mice with tumors with vaccines that activated killer T cells equally, but triggered a different degree of helper T cell activation.
To the surprise of researchers in this latest study, the vaccine intended to hyperactivate helper T cells produced the opposite effect and inhibited tumor rejection.
“We thought that increased activation of helper T cells would optimize clearance of sarcoma tumors in mice,” Sultan said. “Instead, we found that vaccines containing high doses of helper T cells induced inhibitory Tr1 cells that completely blocked tumor clearance. We know that Tr1 cells normally rein in an overactive immune system, but this is the first time they have been shown to put the brakes on its fight against cancer.”
Tr1 cells normally put the brakes on the immune system to stop it from attacking healthy cells in the body, but their role in cancer has not been studied in depth. Examining previously published data, the researchers found that tumors from patients who had responded poorly to immunotherapy had more Tr1 cells compared with tumors from patients who had responded well. The number of Tr1 cells also increased in the mice as the tumors grew, rendering the mice insensitive to immunotherapy.
To avoid the inhibitory cells, the researchers treated vaccinated mice with a drug that enhances the fighting power of killer T cells. The drug, developed by the biotech company Asher Biotherapeutics, contains modifications to the immune-stimulating protein called interleukin 2 (IL-2), which specifically stimulates killer T cells and reduces the toxicity of treatments with unmodified IL-2. The additional boost of the drug overcame the inhibition of Tr1 cells and made the immunotherapy more effective.
“We are committed to personalizing immunotherapy and scaling up its effectiveness,” Schreiber said. “Decades of research into basic tumor immunology have expanded our understanding of how to activate the immune system to achieve the most robust anti-tumor response. This new study expands our understanding of how to improve immunotherapy to benefit more people.”
As co-founder of Asher Biotherapeutics (which provided the mouse version of the modified IL-2 drugs), Schreiber is indirectly involved in the company’s clinical trials testing the human version of the drug as a monotherapy in cancer patients. If successful, the drug has the potential to be tested in combination with vaccines for cancer treatment.