The novelty we are reporting is the ability of this molecule to generate an immune response that patrols the body for the presence of rare tumour cells and to eliminate cancer before it takes hold in the body.
Washington: Scientists say they have identified a molecule that stimulates the immune system and may protect against the development of multiple types of cancer. The recombinant protein molecule SA-4-1BBL has been used to enhance the therapeutic efficacy of cancer vaccines with success in pre-clinical animal models, said researchers from the University of Louisville in the US.
It accomplishes this by boosting the effectiveness of CD8+ T cells, adaptive immune cells trained to target the tumour for destruction, according to the study published in the journal Cancer Research. When the researchers treated normal healthy mice with SA-4-1BBL alone, the mice were protected when they later exposed them to different types of tumour cells.
“The novelty we are reporting is the ability of this molecule to generate an immune response that patrols the body for the presence of rare tumour cells and to eliminate cancer before it takes hold in the body,” said Haval Shirwan, a professor at the University of Louisville.
“Generally, the immune system will need to be exposed to the tumour, recognise the tumour as dangerous, and then generate an adaptive and tumour-specific response to eliminate the tumour that it recognises,” Shirwan said. “Thus, our new finding is very surprising because the immune system has not seen a tumour, so the response is not to the presence of a tumour,” Shirwan said.
The researchers have determined that the molecule generates a tumour immune surveillance system through activation of what is known as CD4+ T cells and innate NK cells, thereby protecting the mice against various cancer types they have never had. This function is an indication of the molecule’s effectiveness in cancer immunoprevention.
In the research mice that had never had cancer were treated with SA-4-1BBL alone, then challenged with cervical and lung cancer tumour cells at various time intervals. The mice showed significant protection against tumour development, with the greatest protection when challenged two weeks after treatment with SA-4-1BBL.
The cancer immunoprevention effect generated by SA-4-1BBL lasted more than eight weeks. “Just giving SA-4-1BBL alone prevents the formation of tumours in animal models,” Shirwan said. “To our knowledge, this is the first study to demonstrate that an immune checkpoint stimulator, known for its function for adaptive immunity, as a single agent can activate an immune system surveillance mechanism for protection against various tumour types,” said Shirwan.
Additional testing showed that CD8+ T cells were not required for the protection, but when CD4+ T and NK cells were eliminated in the mice, protection failed, indicating these two cell types were necessary to achieve the effect. The lack of necessity for CD8+ T cells indicates the process is not one of conventional acquired immunity.
Although the researchers tested the mice for cervical and lung cancers, the protective function of SA-4-1BBL works without the context of specific tumour antigens, giving it the potential to be effective in preventing any number of tumour types. “We are very excited about the cancer immunoprevention possibilities of this molecule. Its effectiveness is not tumour specific, and as a natural ligand, it does not cause toxicity, as is found with 4-1BB agonist antibodies.
“Plus, the fear of autoimmunity is highly minimised, as evident from our data, because it is activating the innate immune cells,” said Esma Yolcu, an associate professor at the University of Louisville. Immune checkpoint stimulators and inhibitors are major regulators of the immune system and work in a similar fashion to the “brake” and “gas” pedals in a vehicle.
Cancer evades the immune system by various means, including immune checkpoint inhibitors, which apply the brake on the immune response against a tumour. Stimulators, on the other hand, serve the accelerator function, improving immune responses against cancer.