Progress of research on γδ T cells in colorectal cancer (Review)

Abstract

Colorectal cancer (CRC) ranks as the third most prevalent malignancy and second leading cause of cancer‑related fatalities worldwide. Immunotherapy alone or in combination with chemotherapy has a favorable survival benefit for patients with CRC. Unlike αβ T cells, which are prone to drug resistance, γδ T cells do not exhibit major histocompatibility complex restriction and can target tumor cells through diverse mechanisms. Recent research has demonstrated the widespread involvement of Vδ1T, Vδ2T, and γδ T17 cells in tumorigenesis and progression. In the present review, the influence of different factors, including immune checkpoint molecules, the tumor microenvironment and microorganisms, was summarized on the antitumor/protumor effects of these cells, aiming to provide insights for the development of more efficient and less toxic immunotherapy‑based anticancer drugs.

Keywords: BTNL; CRC; immunotherapy; microorganisms; γδ T cells.

Figure 1.

Dual effects of drug treatment on Vγ9Vδ2 T-cell cytotoxicity. Proteasome inhibitors, histone deacetylase inhibitors, apoptosis inhibitors, 5-FU and DXR can increase the cytotoxicity of Vγ9Vδ2 T cells against tumor cells by increasing the expression of NKG2D ligands and DR5 on tumor cells, whereas the use of anti-NKG2D mAbs can inhibit the cytotoxicity. Cet-ZA ADCs can activate T-cell receptor-induced tumor cell death. 5-FU, 5-fluorouracil; DXR, doxorubicin; ADC, antibody-drug conjugates; mAb, monoclonal antibody.

Figure 2.

Inhibitory effect of the downregulation of Tet1 on γδ T cells. The presence of hypercholesterolemia can induce miR-101c-mediated oxidative stress, resulting in the downregulation of Tet1 in HSCs. This leads to increased DNA hypermethylation and histone modifications in genes crucial for the differentiation of NKT and γδ T cells. Tet1, Ten Eleven Translocation 1; miR, microRNA; HSCs, hematopoietic stem cells; NKT, natural killer T.

Figure 3.

The structure of BTN3A and its ability to activate Vγ9Vδ2 T cells. The activation of Vγ9Vδ2 T cells by BTN3A1 requires the presence of BTN3A2 or BTN3A3, and the cytotoxicity of Vγ9Vδ2 T cells mediated by BTN3A must involve BTN2A1. ICT01, Periplakin and RhoB play important roles in this activation process.

Figure 4.

Effects of different factors on γδ T-cell activity. In mice, Btnl1 promotes the maturation and proliferation of Vγ7⁺ intraepithelial lymphocytes, whereas Btnl2 recruits IL-17-producing γδ T cells. In humans, the co-expression of BTNL3 and BTNL8 results in a selective T-cell receptor-dependent response in human colon Vγ4⁺ cells. The downregulation of Tet1 results in a decrease in the quantity and functionality of terminally differentiated NKT and γδ T cells. Isopentenyl pyrophosphate accumulation increases the vulnerability of cancer cells to Vγ9Vδ2 T-cell-mediated elimination. IL-2 enhances the expression of NKG2D by inducing DAP10. CD137 co-stimulation can overcome the inhibitory effect of endogenous IL-10 on the antitumor activity of Vγ9Vδ2 T cells. Tim-3 downregulates the expression of perforin and granzyme B in Vγ9Vδ2 T cells. The inhibition of Vδ2 T cells by B7-H3 is mediated mainly by the suppression of T-bet and the downregulation of IFN-γ and perforin/granzyme B expression, which involves STAT3 activation and a reduction in ULBP2 expression. 4H7 and MIH35 can participate in regulating the aforementioned process involving B7-H3. BTN3A plays a role in the antitumor process of γδ T cells as a key mediator of pAg signal transduction. Tet1, Ten Eleven Translocation 1; HSC, hematopoietic stem cell.

Figure 5.

Effects of TME and gut microbiota on antitumor function of γδ T cells. The activated γδ T cells surrounding the hot tumor can secrete immunosuppressive cytokines and express receptors involved in immunosuppression, which can bind to antibodies present on the surface of tumor cells. This leads to depletion of γδ T cells within the TME and promotes tumor progression. Cold tumors are typically surrounded by immunosuppressive cells, such as Tregs and MDSCs, which express IL-10 and TGF-β to suppress the antitumor effect of γδ T cells. TGF-β1 induces differentiation of CD39γδ T cells into CD39γδ Tregs, contributing to adenosine-mediated immunosuppression. Microbes and their metabolites play various roles in this regulatory network. Clostridia and enterotoxigenic Bacteroides fragilis activate tumor-promoting γδ T cells. Phosphatidylethanolamine and phosphatidylcholine, metabolites of Desulfovibrio, induce proliferation of γδ T17 cells. Propionate, a probiotic metabolite, inhibits IL-17 production. Hydroxymethyl-butyl pyrophosphate is used as a phospho-antigen to activate γδ T cells. α-GalCer activates iNKT cells and indirectly induces IFN-γ production by γδ T cells against tumors. TME, tumor microenvironment; Tregs, regulatory T cells; MDSCs, myeloid-derived suppressor cells; iNKT, invariant natural killer T.