Gamma/delta T cells emerge as an untapped resource for cancer immunotherapy

Third lymphocyte lineage shows its mettle

B lymphocytes, a type of white blood cell that is responsible for antibody production, have been at the heart of immunotherapy for decades.  In the 1970s, a breakthrough way of producing ‘immortal’ B cell ‘hybridomas’ enabled researchers to produce vast quantities of antibodies for a particular target of interest.  This paved the way to lifesaving antibody therapies such as Herceptin® (trastuzumab), which treats certain types of breast cancer (specifically, ‘HER2-receptor positive’ breast cancer) by binding to the HER2 receptor.

T lymphocytes, another type of white blood cell, are classed either as ‘alpha/beta T cells’, or ‘gamma/delta T cells’, depending on whether their T cell receptors (TCRs) are composed of alpha and beta chains, or gamma and delta chains.  These classes diverged from each other in the distant past, and thereby constitute separate lymphocyte lineages.  T cells can directly kill infected or cancerous tissues when they bind to diseased cells via their TCRs.  Certain types of leukaemia can now be treated with cultured populations of alpha/beta T cells engineered to express a cancer-targeting TCR.  For instance, a treatment called ‘tisagenlecleucel’ (marketed as Kymriah®) takes the patient’s own alpha/beta T cells, genetically engineers them to express a modified TCR that targets the leukaemia, expands their numbers and then re-infuses them to the patient.

To date, gamma/delta T cells (which are far less abundant than their alpha/beta cousins) have been found to be safe for administration to cancer patients – but largely ineffective.  However, that could be about to change following a paper by Wu and Kyle-Cezar et al published in Science Translational Medicine[i], which identifies and characterises a subpopulation of gamma/delta T cells in breast tissue samples from women with ‘triple negative breast cancer’ (TNBC), a particularly deadly cancer with a historical median survival of ~18 months in the metastatic setting and a poor response to current immunotherapies.

Unlike other breast cancers, TNBCs have prominent immune infiltrates, which suggests an ongoing immunosurveillance. “We recognized that a greater understanding of the immune ecology may open new immunotherapeutic strategies”, says Wu.

The team, led by Professor Adrian Hayday at King’s College London and the Francis Crick Institute, employed several novel techniques to study gamma-delta T-cells that they found residing in the TNBCs.  “We showed they can independently detect and kill cancer cells and secrete IFN-gamma to help other immune cells do the same.”  Using next-generation sequencing, they showed that a particular subset of gamma/delta T cells, called V-delta-1 T-cells’ were enriched in patients with good prognostic outcome, whilst other gamma-delta T-cells were not.  “This degree of granularity in defining gamma-delta T-cell subsets in clinical samples is unprecedented”, says Wu. “Proving that these special cells are present in human breast tissue is an exciting first,” said Kyle-Cezar, joint lead author of this paper. “We knew from animal model studies that gamma/delta cells might play an important role in killing tumours, but this is the first clear evidence that they may do so in human breast cancer.  The discovery opens the door to look at new ways we may be able to tackle this devastating disease.”

Noting that other subtypes of gamma/delta T cells had been used in prior, ultimately ineffective, early phase clinical studies, Wu said “Our study points towards a new, as yet untapped resource, namely V-delta-1 T-cells, which may provide patient benefit either independently or combined with current and future immunotherapies.  Additionally, the presence of V-delta-1 T-cells may be a predictive biomarker for patients who may benefit from other immunotherapies.”

Besides opening up a new avenue for immunotherapy (based on the ‘third lypmphocyte lineage’), Wu and Kyle-Cezar’s findings also suggest an interesting mechanism by which the gamma/delta T cells might exert their anticancer effects.  In contrast to alpha/beta T cells, which see cancer specific mutant proteins via their adaptive TCRs, before exerting their cytotoxic (cell-killing) effects, the gamma/delta T cells identified by Wu and Kyle-Cezar et al instead use conserved innate immune receptors to detect cancer cells independently.

[i] An innate-like Vδ1+ γδ T cell compartment in the human breast is associated with remission in triple-negative breast cancer, Science Translational Medicine, 09 Oct 2019