Scientists say they have discovered a potential new target for immunotherapy of malignant brain tumours, which so far have resisted the ground-breaking cancer treatment based on harnessing the body’s immune system. The discovery, reported in the journal CELL, emerged from laboratory experiments and has no immediate implications for treating patients.
Scientists from Dana-Farber Cancer Institute, Massachusetts General Hospital, and the Broad Institute of MIT and Harvard said the target they identified is a molecule that suppresses the cancer-fighting activity of immune T cells, the white blood cells that seek out and destroy virus-infected cells and tumour cells.
The scientists said the molecule, called CD161, is an inhibitory receptor that they found on T cells isolated from fresh samples of brain tumours called diffuse gliomas. Gliomas include glioblastoma, the most aggressive and incurable type of brain tumour. The CD161 receptor is activated by a molecule called CLEC2D on tumour cells and immunesuppressing cells in the brain, according to the researchers. Activation of CD161 weakens the T cell response against tumour cells.
To determine if blocking the CD161 pathway could restore the T cells’ ability to attack the glioma cells, the researchers disabled it in two ways: they knocked out the gene called KLRB1 that codes for CD161, and they used antibodies to block the CD161-CLEC2D pathway. In an animal model of gliomas, this strategy strongly enhanced the killing of tumour cells by T cells, and improved survival of the animals. The researchers were also encouraged because blocking the inhibitory pathway appeared to reduce T-cell exhaustion – a loss of cell-killing function in T cells that has been a been a major hurdle in immunotherapy.
In addition, “we showed that this pathway is also relevant in a number of other major human cancer types,” including melanoma, lung, colon, and liver cancer, said Kai Wucherpfennig, MD, PhD, director of the Center for Cancer.