Gamma delta T cells are a subset of T cells that promote the inflammatory responses and are an essential component of the immune system. Although gamma delta (γδ) T cells only comprise approximately 5% of all T cells circulating in peripheral blood, they play an important role in fighting cancer. A recent study published in OncoImmunology revealed that the amount of gamma delta T cells that infiltrate a tumor was the best predictor of a favorable outcome for certain types of cancer patients.
Despite the critical role gamma delta T cells play in immunity, researchers do not fully understand the mechanisms that cause proinflammatory functions. Ongoing research involving gamma delta T cells indicates that these cells may hold the key to effective cell therapies that target solid tumors.
Unlike alpha beta T cells, gamma delta T cells do not require donor compatibility to recognize the target cancer antigen. This feature makes gamma delta T cells ideal for off-the-shelf CAR-T therapies that are derived from donors instead of from the patient. An allogeneic approach involving gamma delta T cells could result in a more accessible, effective and affordable immunotherapy for patients.
What Are Gamma Delta T Cells?
The primary T cell type used for CAR-T cell therapies are alpha beta T cells. These conventional T cells are dependent on major histocompatibility complex (MHC)-antigen presentation and display limited targeting of solid tumor cells.
Another T cell type, unconventional, or gamma delta T cells, express a unique T-cell receptor comprised of gamma and delta glycoprotein chains. Unlike alpha beta T cells, the gamma delta T cells are in much lower abundance in the body.
What also makes gamma delta T cells unique is that they can target tumor cells without the need for MHC-antigen presentation. Therefore, they can target cells through a cytotoxic mechanism or by activating other immune cells.
Advantages of Using Gamma Delta T Cells in Immunotherapies
Immunotherapies based on T cells, especially CAR-T cells, have shifted the paradigm in how we treat cancer. These genetically-modified T cells have shown remarkable remission rates in patients with hematological cancers, particularly those who do not respond favorably to conventional treatments. However, the CAR-T cell approach is known for the risk of very serious side effects, limited ability to target solid tumors and scalability challenges.
Current and emerging CAR-T therapies are based on alpha beta T cells, which may be a source of the aforementioned limitations. Gamma delta T cells, on the other hand, are part of body’s innate immune response, which constitutes the first and faster line of defense of the immune system.
The lack of dependence on MHC-antigen presentation makes gamma delta T cells promising tools for the development of allogenic therapies that have a low risk of graft-versus-host disease.
Additionally, gamma delta T cells possess characteristics of both the innate and adaptive immune systems and express a number of receptors that are also found on natural killer cells that have enhanced recognition of tumor cells.
The unique characteristics of gamma delta T cells form the basis of current research in the development of immunotherapies, particularly those focusing on subtypes that infiltrate solid tumors (e.g., Vgamma1 and Vgamma2).
For example, results of research investigating gamma delta T-cell levels in patients with bladder cancer showed that high intratumor gamma delta T-cell proportions (possibly due to Vgamma2 T cells) were associated with better patient survival outcomes, suggesting that Vgamma2 T cells may have an important role in tumor control.
Research on Therapeutic Applications
Understanding the biology of gamma delta T cells may also unlock information that can be harnessed to develop treatments for cancer and cardiovascular disease, the leading causes of death worldwide.
Given the inherent advantages of gamma delta T cells in targeting tumors, several therapeutic approaches (both allogeneic and autologous) have been developed to treat cancer. All of these therapies are currently in pre-clinical or clinical trial stages of development.
Since gamma delta T cells recognize tumor cells independently of HLA antigen presentation, allogeneic (or donor-derived) T-cells have proven to be relatively effective at triggering antitumor immunity with low risk of graft-versus-host disease (GvHD).
In addition to allogenic gamma delta T cell therapies, researchers have studied autologous approaches by incorporating the tumor-targeting mechanism of CAR-T technology with gamma delta T cells. Initial results from these targeted approaches (e.g., Vgamma1 and Vgamma2 studies described above) show great promise and confirm the safety of gamma delta T-cell-based strategies.
Information gathered from studies examining the relationships of immune cell subsets with cardiac function suggests that immunomodulatory treatment approaches may help prevent heart failure in those at risk.
A study measuring peripheral immune cell subsets was conducted in patients with atherosclerosis, and the association of the subsets with left ventricular global circumferential strain (a measure of left ventricular dysfunction) was determined.
The researchers found that the presence of higher proportions of gamma delta T cells was associated with a worse measure of left ventricular global circumferential strain. This insight may help in identifying targets for the developing immunomodulatory therapies to prevent heart failure in high-risk patient populations.
Gamma delta T-cell–based therapies can represent suitable, effective approaches to treat diverse disease states while minimizing serious adverse events. In the near future, results obtained from ongoing clinical trials will determine whether the potential of gamma delta T cells will be translated into clinical benefit.
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 Parker C.M., Groh V., Band H., Porcelli S.A., Morita C., Fabbi M., Glass D., Strominger J.L., Brenner M.B. Evidence for extrathymic changes in the T cell receptor gamma/delta repertoire. J. Exp. Med. 1990;171:1597–1612. doi: 10.1084/jem.171.5.1597.
 Wang J, Lin C, Li H, Li R, Wu Y, Liu H, Zhang H, He H, Zhang W, Xu J. Tumor-infiltrating γδT cells predict prognosis and adjuvant chemotherapeutic benefit in patients with gastric cancer. Oncoimmunology. 2017 Jul 24;6(11):e1353858. doi: 10.1080/2162402X.2017.1353858. PMID: 29147601; PMCID: PMC5674957.
 Kabelitz, D., Serrano, R., Kouakanou, L. et al. Cancer immunotherapy with γδ T cells: many paths ahead of us. Cell Mol Immunol 17, 925–939 (2020). https://doi.org/10.1038/s41423-020-0504-x.
 Chan KF, Duarte JDG, Ostrouska S, Behren A. γδ T Cells in the Tumor Microenvironment-Interactions with Other Immune Cells. Front Immunol. 2022 Jul 11;13:894315.
 “CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers.” National Cancer Institute. Accessed via https://www.cancer.gov/about-cancer/treatment/research/car-t-cells.
 Hato T and Dagher PC. CJASN August 2015, 10 (8) 1459-1469; DOI: https://doi.org/10.2215/CJN.04680514.
 Nguyen S, Chevalier MF, Benmerzoug S, Cesson V, Schneider AK, Rodrigues-Dias SC, Dartiguenave F, Lucca I, Jichlinski P, Roth B, Nardelli-Haefliger D, Derré L. Vδ2 T cells are associated with favorable clinical outcomes in patients with bladder cancer and their tumor reactivity can be boosted by BCG and zoledronate treatments. J Immunother Cancer. 2022 Aug;10(8):e004880.
 Saura-Esteller J, de Jong M, King LA, Ensing E, Winograd B, de Gruijl TD, Parren PWHI, van der Vliet HJ. Gamma Delta T-Cell Based Cancer Immunotherapy: Past-Present-Future. Front Immunol. 2022 Jun 16;13:915837. doi: 10.3389/fimmu.2022.915837. PMID: 35784326; PMCID: PMC9245381.
 Sinha A, Rivera AS, Doyle MF, Sitlani C, Fohner A, Huber SA, Olson NC, Lima JA, Delaney JA, Feinstein MJ, Shah SJ, Tracy RP, Psaty BM. Association of immune cell subsets with cardiac mechanics in the Multi-Ethnic Study of Atherosclerosis. JCI Insight. 2021 Jul 8;6(13):e149193.