Editorial Note

T cells, a rare and distinctive component of the immune system, have been recognized for their potential in cancer immunology and immunotherapy since its discovery. It became obvious in the mid-1980s that the ability of T Cell Receptors (TCR) to undergo somatic recombination in order to identify various antigens is a critical component of adaptive immune responses. TCRs made up of either αβ or γδ chains were identified in quick succession. These preliminary experiments revealed a significant finding: T cells activated via their TCR had the ability to kill cancer cells. Over the last few decades, researchers have discovered that T cells have numerous similarities as well as significant distinctions. T cell biology discoveries, on the other hand, have not kept up with T-cell biology. γδTCR’s molecular targets and functions have largely escaped researchers, mainly due to the fact that γδT cell recognition of cancer cells and their response kinetics differ significantly from αβT cell recognition. γδT cell biology has advanced significantly in recent years, demonstrating the nonredundancy of this lymphocyte fraction, notably in malignancy. γδT cells are being employed as cellular vehicles to target tumors and cancer progression prognostic markers. The papers' goal is to describe novel advances and ways for enhancing T cells' antitumor capabilities, as well as how the expression of their ligands can help with cancer patient prognosis.

γδT cells have a strong propensity to kill the cancer cells, thus researchers are working on ways to improve their cytotoxic activity in the lab. In humans, the Vγ9Vδ2 cell subset detects transformed cells with defective metabolism, predominantly through the upregulation of phosphoantigens resulting from mevalonate pathway anomalies. Isopentenyl Pyrophosphate (IPP) is a phosphoantigen that activates a receptor complex in cancer cells that includes Butyrophilin (BTN)-3A1 and BTN2A1. However, little is known about how this receptor complex and its other interacting partners are displayed on the cell surface. The GTPase, RhoB is important in controlling BTN3A1 appearance on the cell membrane, according to reports. The differential susceptibility of lung tumor cell lines to Vγ9Vδ2 T-cell death was found to be linked with RhoB subcellular and plasma membrane distribution. There are a few ways to improve Vγ9Vδ2 cell identification of cancer cells, the most common of which is to augment the IPP-activated BTN3A1/BTN2A1 complex. Bisphosphonate medicines boost IPP buildup, making cancer cells more vulnerable to Vγ9Vδ2 cell death, but they also promote Vγ9Vδ2 cell proliferation in vitro. For hematological and epithelial-derived cancers, γδT cells are also being outfitted with Chimeric Antigen Receptors (CAR). As with NK CAR cells, CAR T cells are anticipated to be associated with a lower risk of cytokine release syndrome. The ability of CAR T cells to overcome the limited infiltration of tumors by classical αβCAR T cells is yet unknown, and it may rely on the kind of γδ T cells (Vδ1 versus Vδ2), which have naturally different homing tissues. The authors report a new expansion procedure that creates large numbers of pure (> 99%) γδT cells that can be successfully transduced using CAR designs. In-vitro and in-vivo, CD19-directed γδ CAR T cells effectively destroyed CD19+ leukemic cells. A range of pre-clinical models that evaluate killing efficacy are employed to test these numerous tactics whose purpose is to improve γδ T cell cytotoxic function, but these models come with their own set of obstacles. The advantages and disadvantages of the most often utilized pre-clinical models in γδ T cell immunotherapy are summarized. They address the urgent need for improved animal-free in-vitro models such as spheroids and organoids, in addition to using immunodeficient mice transplanted with human tumor cells and γδ T cells.

Another unanswered question in the research is how malignancies can suppress γδ T cell activity. According to several studies, the embryonic-associated molecule, called NODAL, produced by breast cancer cells, has an impact on γδ T cell function. γδ T cells are detected in close proximity to NODAL+ cancer cells in human breast cancers. NODAL expression on breast cancer cell lines lowers γδ T-cell cytotoxicity in gain-of-function and loss-offunction tests. Galectin-3, which is released by cancer cells and inhibits γδ T cell proliferation via α3-β1 integrin, is described as a novel immunosuppressive route in pancreatic cancer. Galectin-3 had no effect on the cytotoxic activity of γδ T cells.