A GD (Gamma-Delta) type of cancel culture

Abstract

γδ T cells represent an 'unconventional' class of CD3+ lymphocytes with unique phenotypical and functional attributes that distinguishes them from their αβ T-cell receptor-expressing counterparts. Studies investigating the roles of γδ T cells in cancer have shown that these cells are indispensable for effective tumor control and their presence within the tumor may be of prognostic significance. Currently, there is significant interest in harnessing γδ T cells for cancer treatment, and research efforts have focused on the development of γδ T-cell-based strategies that are efficacious against cancer. Several therapeutic approaches using γδ T cells have been described, premised on the expansion of γδ T cells or γδ chimeric antigen receptor T therapy. The potential for broad, unbiased and 'off-the-shelf' applicability in cancer treatment, drives ongoing and future research and methodologies by which γδ T cells can be exploited for therapeutic use. In this review, we will briefly outline the characteristics of γδ T cells and describe how these work within and promote proper functioning of the cancer-immunity cycle. Additionally, we will introduce strategies that are less commonly described and may potentially be more efficacious than other types of therapy. Our discussion will expand upon presently known applications and even highlight the versatility of this immune subset as cancer therapeutics. γδ T-cell-based treatment is an emerging strategy and should be considered for cancelling cancer.

Keywords: T-cell product manufacturing/scalability; T-cell therapy for patients with solid tumors; tumor-infiltrating lymphocytes (TIL).

Figure 1

The multifaceted functions of γδ T cells compliment the cancer-immunity cycle. (A) γδ T lymphocytes function as APCs. Tumor-associated antigens that are released by apoptotic cancer cells are taken up by γδ T cells, processed and cross-presented to αβ T cells. These αβ T cells become activated and induce antitumor responses. (B) γδ T cells naturally home to tissues. γδ T cells express various chemokine receptors and tissue-associated molecules on their cell surface that underlies their tropism for specific anatomical regions. Such tissue-homing abilities may circumvent complications related to T_eff cell ‘homing deficit’ during immunotherapy wherein the expanded γδ T population can naturally traffic to the tumor site for efficient tumor eradication. (C) Unique mode of antigen recognition by γδ T cells. γδ cells interact with non-peptide ligands such as lipid or other stress-related molecules bound to non-classical, MHC-like molecules such as CD1 family proteins. (D) Direct and indirect mechanisms of γδ T-cell-mediated tumor killing. These cells can directly kill cancer cells via ADCC, death receptor engagement or secretion of cytotoxic molecules, or carry out T ‘helper’ functions and induce other immune cell types. ADCC, antibody-dependent cellular cytotoxicity; APC, antigen-presenting cells; IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; MICA/B, MHC class I chain-related proteins A and B; NKR, natural killer receptor; TCR, T-cell receptor; TNF, tumor necrosis factor.