Application of double-negative T cells in haematological malignancies: recent progress and future directions

Abstract

Haematologic malignancies account for a large proportion of cancers worldwide. The high occurrence and mortality of haematologic malignancies create a heavy social burden. Allogeneic haematopoietic stem cell transplantation is widely used in the treatment of haematologic malignancies. However, graft-versus-host disease and relapse after allogeneic haematopoietic stem cell transplantation are inevitable. An emerging treatment method, adoptive cellular therapy, has been effectively used in the treatment of haematologic malignancies. T cells, natural killer (NK) cells and tumour-infiltrating lymphocytes (TILs) all have great potential in therapeutic applications, and chimeric antigen receptor T (CAR-T) cell therapy especially has potential, but cytokine release syndrome and off-target effects are common. Efficient anticancer measures are urgently needed. In recent years, double-negative T cells (CD3⁺CD4^-CD8^-) have been found to have great potential in preventing allograft/xenograft rejection and inhibiting graft-versus-host disease. They also have substantial ability to kill various cell lines derived from haematologic malignancies in an MHC-unrestricted manner. In addition, healthy donor expanded double-negative T cells retain their antitumour abilities and ability to inhibit graft-versus-host disease after cryopreservation under good manufacturing practice (GMP) conditions, indicating that double-negative T cells may be able to be used as an off-the-shelf product. In this review, we shed light on the potential therapeutic ability of double-negative T cells in treating haematologic malignancies. We hope to exploit these cells as a novel therapy for haematologic malignancies.

Keywords: ACT; Allo-HSCT; DNT cells; GVHD; Hematologic malignancies.

Fig. 1

The timeline of studies in development of DNTs function in immunoregulation and anticancer. Since the discovery of DNTs in 1984, a lot of research have been performed in DNTs development and function. DNTs, double negative T cells; GVHD, graft-versus-host disease; GVL, graft-versus-leukaemia

Fig. 2

The regulatory and antitumor functions of DNTs. The antitumor functions of DNTs depend on expression of FasL, NKG2D, DNAM-1, TRAIL and NKp30. Moreover, secretion of IFN-γ, TNF-α, granzyme B and perforin take an important place. In addition, DNTs can mediate many types of immunocyte and exert immunoregulatory functions. DNTs downregulate expression of CD80/CD86 in dendritic cell and impact their interaction with other cells. DNTs can express MHC-peptide complex which expressed in dendritic cell by trogocytosis way, then interact with T cell and kill them through Fas/Fas L manner. Granzyme B and perforin secretion by DNTs induce death of T cell and B cell. Alternatively, DNTs kill M1 macrophage by down-regulating TNF-α and IFN-γ secretion of M1. FasL, Fas ligand; TNF-α, tumor necrosis factor α; NKG2D, natural killer group 2-member D; TRAIL: tumour necrosis factor-related apoptosis-inducing ligand