Current cancer immunotherapies are primarily predicated on αβ T cells, with a stringent dependence on MHC-mediated presentation of tumour-enriched peptides or unique neoantigens that can limit their efficacy and applicability in various contexts. After two decades of preclinical research and preliminary clinical studies involving very small numbers of patients, γδ T cells are now being explored as a viable and promising approach for cancer immunotherapy. The unique features of γδ T cells, including their tissue tropisms, antitumour activity that is independent of neoantigen burden and conventional MHC-dependent antigen presentation, and combination of typical properties of T cells and natural killer cells, make them very appealing effectors in multiple cancer settings. Herein, we review the main functions of γδ T cells in antitumour immunity, focusing on human γδ T cell subsets, with a particular emphasis on the differences between Vδ1+ and Vδ2+ γδ T cells, to discuss their prognostic value in patients with cancer and the key therapeutic strategies that are being developed in an attempt to improve the outcomes of these patients.
Human γδ T cells comprise subsets with distinct tissue tropisms: Vδ1+ cells are enriched in mucosal tissues (and often predominate within carcinomas), whereas Vδ2+ cells are most abundant in the blood and lymphoid organs.
Most human γδ T cells have antitumour functions, but have also been reported to have pro-tumour properties in specific contexts.
γδ T cells have prognostic value in patients with cancer, being associated with favourable outcomes for most tumour types, especially when focusing on Vδ1+ cells.
γδ T cells are endowed with antitumour mechanisms of both αβ T cells and natural killer (NK) cells, mediated not only by T cell receptor (TCR) and co-stimulatory signals but also by activating NK cell receptors.
γδ T cells mostly act in a manner independent of MHC class I-mediated antigen presentation, making them suitable for treatment of MHC class I-deficient tumours, as well as for application in allogeneic settings.
Emerging therapeutic approaches based on γδ T cells comprise cell engagers, adoptive transfer of expanded Vδ1+ or Vδ2+ T cell subsets, and genetic engineering of γδ T cells to express chimeric antigen receptors (CARs) or αβ T cells to express specific γδTCRs.
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The authors thank A. Hayday (King’s College London) for insightful discussions on this topic, and acknowledge funding from the Fundação para a Ciência e Tecnologia of the Portuguese Ministério da Ciência, Tecnologia e Ensino Superior (PTDC/MED-ONC/6829/2020 to B.S.-S. and 2021.01953.CEECIND to S.M.).
The authors receive funding from a sponsored research agreement with Takeda Development Center Americas, Inc, Lexington, MA.
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Mensurado, S., Blanco-Domínguez, R. & Silva-Santos, B. The emerging roles of γδ T cells in cancer immunotherapy. Nat Rev Clin Oncol 20, 178–191 (2023). https://doi.org/10.1038/s41571-022-00722-1