Lung cancer affects approximately 48,500 persons in the United Kingdom every year. New treatments are urgently needed because only around 20% of patients live 5 years after diagnosis, and it is the leading cause of cancer death.
Researchers from King’s, the Francis Crick Institute, and UCL explored the involvement of specialized immune cells known as gamma delta (γδ) T cells in lung cancer in a paper published today in Nature Cancer.
γδ T cells are unique from the more common “conventional” T cells that are frequently implicated in cancer-fighting. These cells are distinct in that they are abundant in the tissues from which malignancies arise, as well as in their ability to respond to “stress” signals that are expressed by practically all cancer cells.
Researchers have previously demonstrated that when these immune cells are stimulated by stress signals, they can destroy malignant cells in a petri dish. This implies they are in a good position to detect and prevent tumors from growing.
The scientists analyzed samples of lung tumors and non-cancerous lung tissue from 25 patients with non-small-cell lung cancer as part of the TRACERx trial, which was supported by Cancer Research UK. They discovered that Vδ1 cells, a subtype of γδ T cells, were detectable in both malignant and non-cancerous lung tissue.
Their existence within the tumor was linked to cancer-free survival following surgery (remission). However, their presence in non-cancerous tissue was a better predictor of continued remission, indicating that these cells continue to fight cancer even after the tumor has been removed.
The researchers also proved that these cells produce the appropriate chemicals to eradicate tumor cells within the tumor, which had previously only been shown in controlled circumstances. They discovered that Vδ1 T cells possessed stem-like characteristics that could allow them to self-replenish within tumors, which is crucial for long-term tumor management.
The researchers examined data from roughly 800 non-small-cell lung tumors in The Cancer Genome Atlas, a big public database, to see how these cells affected lung cancer survival. They found that individuals with high numbers of Vδ1 T cells in their lung tumor were more likely to sustain by using the expression of a specific gene as an indicator of Vδ1 T cell levels.
Researchers also looked at data from the INSPIRE clinical study, which showed that patients with more Vδ1 T cells in their solid tumors were more inclined to answer to pembrolizumab, an immunotherapy drug.
It’s less than three years since we showed that people with high levels of Vd1 in their breast tumor were more likely to remain disease-free. We’ve now also uncovered their important role in lung cancer, on the heels of other studies implicating their importance in ovarian cancer.”
Adrian Hayday, Professor, School of Immunology & Microbial Sciences, King’s College London
Hayday added, “While more research is needed to understand and harness the anti-cancer properties of these cells, this work is a positive development for oncologists considering how the cells might best be applied in both the prognosis and treatment of many different patients.”
Immunotherapies are important tools for treating cancer, however sadly in the case of lung cancers they often do not work for a long period and it is hard for doctors to predict which patients will benefit from these treatments. This work adds to the body of evidence of the importance of T cells, in this case Vδ1’s, in protection from disease relapse after surgery.”
Charlie Swanton, Co-Senior Author, King’s College London
Swanton was also the group leader at the Crick and UCL Chief Investigator of TRACERx and Chief Clinician at Cancer Research UK.
“By better understanding how gamma delta T cells and the wider immune system work in the face of cancer and response to treatments, we hope to uncover potential new ways to tackle the disease and offer more hope to patients,” he said.
Important insights concerning the nature and biology of these distinct immune cells in human lungs were also discovered by the study, which could have consequences for future patient safety. They discovered that Vδ1 T cells, which are more abundant in the blood, are more prevalent in the lungs than Vδ2 T cells, which are more common in the blood. Only Vδ1 T cells were a reliable predictor of survival.
Yin Wu, study lead author, Wellcome Trust Clinical Research Career Development Fellow, and honorary consultant medical oncologist, says “This understanding could help explain why previous clinical trials using γδ T cells to treat lung cancers have not been very successful, as these have used therapies derived from the Vδ2 subset.”
Patients with blood malignancy are already being treated with gamma delta T cell treatments in early-stage clinical trials. Adrian Hayday co-founded Gamma Delta Therapeutics, which hopes to harness the activity of these cells to generate “off-the-shelf” cell therapies for a variety of malignancies and auto-inflammatory illnesses.
Wu, Y., et al. (2022) A local human Vδ1 T cell population is associated with survival in nonsmall-cell lung cancer. Nature Cancer. doi.org/10.1038/s43018-022-00376-z.