γδ T Cells for Leukemia Immunotherapy: New and Expanding Trends

Abstract

Recently, many discoveries have elucidated the cellular and molecular diversity in the leukemic microenvironment and improved our knowledge regarding their complex nature. This has allowed the development of new therapeutic strategies against leukemia. Advances in biotechnology and the current understanding of T cell-engineering have led to new approaches in this fight, thus improving cell-mediated immune response against cancer. However, most of the investigations focus only on conventional cytotoxic cells, while ignoring the potential of unconventional T cells that until now have been little studied. γδ T cells are a unique lymphocyte subpopulation that has an extensive repertoire of tumor sensing and may have new immunotherapeutic applications in a wide range of tumors. The ability to respond regardless of human leukocyte antigen (HLA) expression, the secretion of antitumor mediators and high functional plasticity are hallmarks of γδ T cells, and are ones that make them a promising alternative in the field of cell therapy. Despite this situation, in particular cases, the leukemic microenvironment can adopt strategies to circumvent the antitumor response of these lymphocytes, causing their exhaustion or polarization to a tumor-promoting phenotype. Intervening in this crosstalk can improve their capabilities and clinical applications and can make them key components in new therapeutic antileukemic approaches. In this review, we highlight several characteristics of γδ T cells and their interactions in leukemia. Furthermore, we explore strategies for maximizing their antitumor functions, aiming to illustrate the findings destined for a better mobilization of γδ T cells against the tumor. Finally, we outline our perspectives on their therapeutic applicability and indicate outstanding issues for future basic and clinical leukemia research, in the hope of contributing to the advancement of studies on γδ T cells in cancer immunotherapy.

The Mysterious Actor—γδ T Lymphocytes in Chronic Lymphocytic Leukaemia (CLL)

“…In contrast to ɑβ T cells, γδ T lymphocytes recognise tumour cells independently of HLA restrictions [ 48 ]. γδ T cells express a variety of recognition receptors apart from their TCR-KG2D is uniformly expressed by all three major subsets, namely, Vδ1, Vδ2 and Vδ3 [ 49 ]. Knowledge about the recognition/activation receptors on cells in Vδ3 is currently limited.…”

“…Nevertheless, there are still significant challenges that have to be overcome, e.g., choosing the best method for in vitro expansion (i.e., one that offers a very high yield of highly active γδ T cells). Current approaches range from a simple zoledronate + IL-2 regimen through PHA stimulation to a complex approach with numerous cytokines used, as proposed by Almeida et al [ 48 , 49 , 93 ].…”

Harnessing Unconventional T Cells and Innate Lymphoid Cells to Prevent and Treat Hematological Malignancies: Prospects for New Immunotherapy

“…The acquisition of new knowledge in the field of the antineoplastic capabilities of γδ cells means that their employment in CML could be hypothesized [ 112 ]. When CML cells are cultured with zoledronic acid (ZOL) + IL-2 + IFN type I, their toxic effects are augmented and Vγ9Vδ2 cells may be able to effectively kill myeloid leukemia cells [ 113 ].…”

High TRGV 9 Subfamily Expression Marks an Improved Overall Survival in Patients With Acute Myeloid Leukemia

“…Nowadays, according to their TRD (TCRδ) chain usage, human γδ T cells are mainly divided into 2 major subsets including Vδ1 and Vδ2 in peripheral blood (PB). Several functional TRG (TCRγ) gene segments are generally divided into Vγ2, γ3, γ4, γ5, γ8, γ9, γ10 (also termed TRGV 2, TRGV 3, TRGV 4, TRGV 5, TRGV 8 , TRGV 9 and TRGV10 , respectively) ( 12 , 13 ). The V-genes of TRGV 2-5 and TRGV 8 have a relatively high sequence similarity, which are different from TRGV 9 sequences.…”

“…Although Vδ1 T cells are predominantly associated with the Vδ1 comprising TRGV 2, TRGV 3, TRGV 4, TRGV 5, TRGV 8 , which belonging to TRGV I subsets, the majority of Vδ2 T cells express an invariant TCR harboring TRGV 9 , which belonging to TRGV II subsets ( 15 ). In addition, TRGV 10 belongings to TRGV III subsets ( 12 ). In the PB of healthy individuals (HIs), there is a predominant expression in the γδ T cell population, which is the cell expressing Vγ9 together with Vδ2, termed Vγ9 + Vδ2 + T cells ( 15 , 16 ).…”