A rare subset of T cells called V-delta 1 gamma-delta (Vd1-gd) T cells could help predict which patients with advanced skin cancer may be responsive to immunotherapy, according to a novel study published by Davies et al in Nature Cancer. The new findings may lead to the development of new and more effective treatment options for patients with melanoma who do not benefit from current immunotherapies.
Background
When advancing, cancer cells are capable of targeting checkpoint proteins on immune cells to weaken the body’s immune response. As a result, the immune cells responsible for attacking cancer cells are considered suppressed and deactivated, allowing the cancer to grow unchecked. Previous studies have shown that immune checkpoint inhibitors can reactivate T cells formerly suppressed by cancer cells and block the pathways to the checkpoints on T cells.
The T cells can then kill cancer cells by recognizing cancer cell mutations not present in healthy cells. This treatment strategy can sometimes cure patients with metastatic cancer; however, most patients with advanced cancers do not benefit from immune checkpoint inhibitors and the treatments can often cause lifelong side effects.
“The number of cancer mutations can sometimes help [physicians] identify the patients most likely to benefit from [immune checkpoint inhibitor] 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,” explained co–senior study author Yin Wu, PhD, a Wellcome Trust clinician scientist at King’s College London and an honorary consultant medical oncologist at Guy’s Hospital.
Vd1-gd T cells 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 PD-1 immune checkpoint protein.
Study Methods and Results
In the new study, researchers analyzed the clinical trial data of 127 patients with melanoma who were treated with immune checkpoint inhibitors that targeted the PD-1 immune checkpoint.
The researchers found that the presence of Vd1-gd T cells was highly predictive of positive responses to immune checkpoint inhibitor therapy—particularly in patients whose tumors harbored few mutations. They then used a novel technique to isolate and grow Vd1-gd T cells from human tissues and demonstrated that the cells could be reactivated by immune checkpoint inhibitor therapies currently used in the National Health Service to treat patients with advanced skin cancer.
Further, the researchers discovered that the Vd1-gd T cells could be more resistant to suppression from cancer cells compared with more common T cells, representing the potential for therapies using Vd1-gd T cells to work for longer periods of time.
Conclusions
“The study findings may help [physicians] decide which patients are most likely to benefit from current immunotherapies. These therapies are both costly and importantly can cause severe and lifelong side effects, so it is important to be able to predict when they will actually work,” emphasized co–lead study author Shraddha Kamdar, MSc, PhD, a research fellow at King’s College London.
“Our study highlights the importance of understanding the contributions of lesser-studied immune cell types in efforts to improve the effectiveness immunotherapies,” underscored co–lead study author Daniel Davies, MBBS, a PhD student at King’s College London.
The ability to predict whether a patient will have a high chance of responding to immunotherapy could save medical service providers from ordering costly treatments that may not work and help prevent patients from undergoing potentially toxic treatments that won’t fight their cancer.
“Collaboration is key to any scientific study, and this project shows the benefit of working together across institutions. The study’s results are striking and strongly support ongoing efforts to directly infuse Vd1-gd T cells into patients with cancer, an approach pioneered at King’s College London and the Francis Crick Institute,” concluded co–senior study author Adrian Hayday, FRS, FMedSci, PhD, Professor of Immunobiology at King’s College London and Principal Group Leader at the Francis Crick Institute.
Disclosure: For full disclosures of the study authors, visit nature.com.
