Gamma delta T cells – staying awake when other T cells have gone to sleep CREDIT [Nature Cancer, photographer Dr. Joe Brock]

Researchers from King’s College London, Guy’s and St Thomas’ Hospital Trust, and the Francis Crick Institute have discovered a rare type of T immune cell that can help predict whether a patient with advanced skin cancer may benefit from immunotherapy treatments.

The study was published in Nature Cancer, in an article titled, “PD-1 defines a distinct, functional, tissue-adapted state in Vδ1+ T cells with implications for cancer immunotherapy.”

“Checkpoint inhibition (CPI), particularly that targeting the inhibitory coreceptor programmed cell death protein 1 (PD-1), has transformed oncology,” the researchers wrote. “Although CPI can derepress cancer (neo)antigen-specific αβ T cells that ordinarily show PD-1-dependent exhaustion, it can also be efficacious against cancers evading αβ T cell recognition. In such settings, γδ T cells have been implicated, but the functional relevance of PD-1 expression by these cells is unclear. Here we demonstrate that intratumoral TRDV1 transcripts (encoding the TCRδ chain of Vδ1+ γδ T cells) predict anti-PD-1 CPI response in patients with melanoma, particularly those harboring below average neoantigens.”

Previous research has shown that immune checkpoint inhibitors (ICIs) can “reactivate” T cells formerly suppressed by cancer cells. The T cells can then kill cancer cells by recognizing cancer cell mutations not present in healthy cells. However, most patients with advanced cancers do not benefit from ICIs.

Co-senior author Yin Wu, PhD, a Wellcome Trust clinician scientist at King’s College London and honorary consultant medical oncologist at Guy’s Hospital, said: “The number of cancer mutations can sometimes help doctors identify the patients most likely to benefit from ICI therapy but curiously, some cancers with very few mutations can still respond very well. Our research team reasoned that these successes must be due to other immune cells that can see cancer cells even in the absence of lots of mutations.”

The researchers discovered a rare subset of T cells, Vd1-gd T cells, that can recognize and kill cancer cells without needing them to have mutations for identification. These T cells can be found inside tumors where they also have a specific type of immune checkpoint protein, PD-1.

The researchers analyzed clinical trial data from 127 patients with melanoma who were treated with ICIs that targeted the “PD-1” immune checkpoint and found that the presence of Vd1-gd T cells was highly predictive of positive responses to ICI therapy, particularly in cancers with few mutations. The team then used a new technique to isolate and grow these cells from human tissues and were able to show for the first time that the Vd1-gd T cells can be reactivated by ICI therapies currently used in the NHS to treat patients with advanced skin cancer.

“The study findings may help doctors decide which patients are most likely to benefit from current immunotherapies,” said co-first author Shraddha Kamdar, PhD, a research fellow at King’s. “These therapies are both costly and importantly can cause severe and life-long side effects, so it is important to be able to predict when they will actually work.”

The team also found evidence that the Vd1-gd T cells could be more resistant to suppression from cancer cells compared with more common T cells