Translating Unconventional T Cells and Their Roles in Leukemia Antitumor Immunity

Abstract

Recently, cell-mediated immune response in malignant neoplasms has become the focus in immunotherapy against cancer. However, in leukemia, most studies on the cytotoxic potential of T cells have concentrated only on T cells that recognize peptide antigens (Ag) presented by polymorphic molecules of the major histocompatibility complex (MHC). This ignores the great potential of unconventional T cell populations, which include gamma-delta T cells (γδ), natural killer T cells (NKT), and mucosal-associated invariant T cells (MAIT). Collectively, these T cell populations can recognize lipid antigens, specially modified peptides and small molecule metabolites, in addition to having several other advantages, which can provide more effective applications in cancer immunotherapy. In recent years, these cell populations have been associated with a repertoire of anti- or protumor responses and play important roles in the dynamics of solid tumors and hematological malignancies, thus, encouraging the development of new investigations in the area. This review focuses on the current knowledge regarding the role of unconventional T cell populations in the antitumor immune response in leukemia and discusses why further studies on the immunotherapeutic potential of these cells are needed.

Figure 1

Overview of subpopulations, important receptors, and cytokines produced by γδ T cells. γδ T cells express some receptors that are essential for the tumor recognition and destruction, which gives a certain advantage when compared to other conventional T lymphocyte populations, either due to MHC independence or due to the high expression of the receptors mentioned in the image. The antileukemic recognition repertoire includes several molecules, such as NKG2D, NCRs, FasL, CD16, DNAM-1, and the TCR γδ itself.

Figure 2

Overview of subpopulations, important receptors, and cytokines produced by NKT cells. Unlike conventional NK cells that mature in the bone marrow, NKT cells develop in the thymus and acquire an invariant or variant TCR, through which their subgroups are stratified. Recent studies show that these lymphocytes participate in the antitumor immune response by recognizing CD1d+ tumors and secreting Th1, Th2, and Th17 profile cytokines.

Figure 3

Overview of subpopulations, important receptors, and cytokines produced by MAIT cells. MAIT cells develop in the thymus, where they acquire a semi-invariant TCR, restricted to MR1. In humans, they can be categorized into five subsets based on the expression of the CD4 and CD8 coreceptors, with CD4⁻ CD8αα⁺ or CD4⁻ CD8αβ⁺ being the most abundant, collectively corresponding to approximately 80% of MAIT cells. They produce a repertoire of Th1 and Th17 cytokines (IFN-γ, TNF, IL-2, IL-17A, and IL-22), in addition to perforins and granzymes B, and express various cytokine, chemokine, and homing molecules.