The Rising Star of Cancer Immunotherapy—Gamma Delta T Cells

On March 25, 2021, a Dutch biotechnology company was listed on the Nasdaq with an initial public offering (IPO) of more than 100 million US dollars. The proceeds of the IPO will be used to promote the development of a bispecific antibody pipeline, which is designed to treat cancer by a rare type of immune T cell—Gamma-delta T cell. So what are Gamma-delta T cells? Why are the investors and scientists so interested in Gamma-delta T cell therapy for cancer treatment?

Immune T cells are the main focus of cancer immunotherapy. Most T cell research and clinical applications are centered on?? T cells and?? T cell receptors (TCR) (accounting for 65%–70% of T cells), but in fact, T cells expressing Gamma-delta TCR (0.5%–5% of all T lymphocytes) also play an important role in cancer immunity.

"Although still in an earlier stage compared to other types of T cells, the research history of Gamma-delta T cells is not that short. It was first discovered in 1984, and since 2018, many researchers have paid much attention and conducted research on them," introduced by a scientist at Creative Biolabs, a biotech company focusing on tailored Gamma-delta T cell services.

Gamma-delta T cells are natural surveillance cells of the immune system, constantly patrolling in the human body, identifying and targeting tumor cells. These cells also play a role in bridging the innate immune system and the adaptive immune system. Gamma-delta T cells and?? T cells have many things in common, for example, they can all exert cytotoxic effect and produce pro-inflammatory cytokines. The biggest difference between the two is their relative dependence on the major histocompatibility complex (MHC) molecules.?? T cells can specifically recognize non-self or tumor neoplastic polypeptide antigens presented by MHC molecules on the surface of target cells through their surface receptor TCR, which is one of the core theories of modern immunotherapy. In contrast, Gamma-delta T cells can recognize their target antigens without being restricted by MHC, and mediate anti-tumor responses without causing graft-versus-host disease (GVHD).

Compared with?? T cells, Gamma-delta T cells have several advantages. First of all, as mentioned above, Gamma-delta T cells recognize their target cells in a manner independent of MHC, thereby reducing the risk of allogeneic reactions and GVHD.

Secondly, Gamma-delta T cells infiltrate a variety of tissues, which can quickly respond to targets and release effector cytokines. Among them, the v?1 Gamma-delta T cell, in particular, has a homing advantage over?? T cells, and can better infiltrate and function in a hypoxic tumor environment.

Thirdly, the recognition and killing of tumors by Gamma-delta T cells do not depend on the expression of a single antigen. On the contrary, they recognize multiple antigens on various cancer cells through various innate cytotoxic receptors expressed on the cell membrane, which expands the range of targets that can be used to kill tumor cells, reducing the possibility that the miss of single antigens leads to immunity escape. This advantage also provides an opportunity to design immunotherapies for tumors lacking a clear neoantigen, thereby eliminating the need for further genetic engineering of effector cells.

Although major breakthroughs have been made in current immunotherapy, CAR-T cell therapy based on?? T cells is limited in the treatment of solid tumors. Since the discovery of Gamma-delta T cells in 1984, the academic community has explored more and more about the characteristics of Gamma-delta T cells. Scientists believed that research on these cells will contribute to cancer immunotherapy, and the increasing interest of the capital market in this field also makes them a rising star in cancer treatment discovery.

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