γδ T Cell Therapy Development for Colorectal Cancer

Colorectal cancer is a common malignant tumor of the gastrointestinal tract, and its incidence accounts for third place among gastrointestinal tumors. Because of its strong metastasis and lack of obvious early symptoms, the mortality rate of colorectal cancer is extremely high. Surgery is the most effective treatment for early-stage colorectal cancer. However, many patients have already metastasized when they are diagnosed. For these patients, chemotherapy or immunotherapy is an indispensable alternative therapy. Recently, γδ T cell therapy, as promising anti-tumor immunotherapy, has attracted the attention of scientists. However, it may not be suitable for colorectal cancer since it has been investigated as a risk factor for colorectal tumorigenesis.

γδ T Cell

The γδ T cell receptor TCRγδ is a heterodimer composed of a γ chain and a δ chain. The γ chain and the δ chain are encoded by the γ gene and the δ gene, respectively. Each peptide chain has two immunoglobulin-like domains: the amino-terminal variable region (V region) domain and the carboxy-terminal constant region (C region) domain. According to the expression of TCRγδ chains, γδ T cells can be divided into two subgroups: Vδ1T cells and Vδ2T cells. Vδ1T cells have different Vγs, which are mainly distributed in the epithelium and mucosa, while Vδ2T cells mainly exist in the peripheral blood.

γδ T cells are a relatively small type of T lymphocytes, accounting for about 1%-10% of human peripheral blood lymphocytes. Its role is between innate immunity and adaptive immunity, and is not subject to the restriction of MHC class I and II molecules and their related antigen peptide ligands. Thus, γδ T cells do not depend on the process of antigen processing and presentation, and can directly recognize antigens. They can dissolve target cells by secreting cytokines such as perforin, granzyme B, Fas/FasL pathway, etc. to exert its anti-infection, anti-tumor, and autoimmune disease effects, while has no cytotoxic effect on normal cells.

γδ T Cell and Colorectal Cancer

In 2010, Wu et al. elucidated the role and mechanism of γδ T17 cells in the inflammatory immune microenvironment of human colorectal cancer. They collected more than 100 samples from colorectal cancer patients at different stages. Through a series of detection techniques such as primary cell separation and culture, multicolor flow cytometry analysis and sorting, they found that human colorectal cancer tissues IL-17 is significantly elevated, and it is mainly derived from tumor-infiltrating γδ T17 cells, rather than helper T cells (Th)17 proposed by animal model studies, clarifying the source of human colorectal cancer IL-17. Further studies have also shown that the intestinal bacteria and their products caused by the destruction of the epithelial integrity of colorectal cancer tissues invade tumor tissues, which can activate infiltrating inflammatory dendritic cells (InfDC) to secrete IL-23, thereby inducing polarization and abnormality increase of γδ T17 cells. In addition to secreting cytokine IL-17, γδ T17 cells can also secrete IL-8, tumor necrosis factor (TNF)-α and granulocyte-macrophage colony-stimulating factor (GM-CSF). These cytokines result in the accumulation of immunosuppressive cells (PMN-MDSC) in tumor tissues and promote these cells proliferation and survival, thereby forming an immunosuppressive microenvironment, which in turn leads to tumor progression. For this reason, the researchers proposed the mechanism of action of γδ T17/PMN-MDSC immune regulation axis.

Besides, based on the clinicopathological characteristics of patients with colorectal cancer, the researchers analyzed the clinical significance of changes in γδ T17 cells, and found that only γδ T17 cells were infiltrated, not Th17 or Tc17 cells, and were related to poor clinical prognosis related indicators such as TNM stage, tumor size, and lymph. It is positively correlated with vascular invasion, indicating that the more γδ T17 cells in the tumor tissue and the higher the proportion, the higher the degree of tumor malignancy and the worse the clinical prognosis.

Fig.1 The yd T17 cells in normal tissue (N), tumor border (TB), and intratumor (INT) detected by FCM. (Wu, 2014)

γδ T cell in Colorectal Cancer Therapy

The existing evidence showed that γδ T cells have a strong anti-tumor function in vitro and in vivo. Using γδ T cells expanded in vitro for tumor cell immunotherapy can effectively control or relieve the tumor patients with very few cells or severely defective γδ T cell function. However, there are still many unknowns about the application of γδ T cell therapy in the treatment of colorectal cancer. The above-mentioned study by Wu et al. fills the gap in the study of γδ T17 cells in colorectal tumors, and also provides the possibility for tumor treatment and prognosis prediction by targeting γδ T17 cells, which guides new strategies for future clinical transformation. If you are exploring the application of γδ T cell therapy in colorectal cancer, Creative Biolabs will provide you with a full range of guidance and assistance.

Services at Creative Biolabs

• γδ T Cell Receptors Services (e.g., γδ TCR Repertoires Analysis Services, and γδ TCR Transcriptome Analysis Services)
• γδ T Cell Development Services (e.g., γδ T Cell Isolation Services and γδ T Cell Activation and Expansion Services)
• γδ T Cell Engineering Services (e.g., CAR Engineered γδ T Cell Development Services and αβ TCR-Engineered γδ T Cells Development Services)

Creative Biolabs has experts in different directions in the field of new drug research and development. Through cooperation with numerous customers, we accumulated a lot of research and development experience in the field of cell therapy. If you are exploring the application of γδ T cell therapy in colorectal cancer, please contact us. Creative Biolabs will provide you with a full range of guidance and assistance.

Reference

1. Wu, P.; et al. γδ T17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer. Immunity. 2014, 40(5), 785-800.