Immune regulatory networks and therapy of γδ T cells in liver cancer

Liver cancer is a highly malignant tumor with significant global mortality, causing hundreds of thousands of deaths annually and posing a serious socioeconomic burden. The pathogenesis of liver cancer remains unclear and is closely tied to its complex tumor microenvironment (TME). The interaction between protumor and antitumor factors, along with cellular and noncellular components, forms a multicellular network in the TME, collectively influencing the malignant behavior of liver cancer cells. Due to late diagnosis, many patients miss the opportunity for surgical resection, resulting in poor prognosis. Immunotherapy, especially cellular immunotherapy involving NK cells, CAR-T cells, and γδ T cells, has shown promise in improving liver cancer treatment outcomes.

Human γδ T cells are categorized into Vδ1+, Vδ2+, and Vδ3+ subtypes based on the arrangement of their γ and δ chains. Vδ1+ γδ T cells are primarily found in the epithelium and mucosa, constituting 5-10% of γδ T cells, and exhibit a CD45RA+CD27+ phenotype with high CD56 expression in healthy individuals. Vδ2+ γδ T cells are predominantly in peripheral blood, with the Vγ9Vδ2 TCR subset accounting for 50-95% of γδ T cells, and display a CD45RA-CD27+ phenotype, facilitating rapid migration to inflammatory sites. Vδ3+ γδ T cells, although less studied, are mainly located in the liver and small intestine epithelium.

γδ T cells exhibit diverse biological functions, including cytotoxic activity against target cells, cytokine and chemokine secretion, and interaction with various immune cells like αβ T cells, dendritic cells (DCs), B cells, NK cells, and macrophages. These functions enable γδ T cells to contribute to anti-infection and antitumor responses, immune regulation, and tissue repair. Key cytokines produced by γδ T cells, such as IFN-γ and TNF-α, play crucial roles in their antitumor effects. Recognition mechanisms involving γδ TCRs and NK cell receptors, along with antibody-dependent cell-mediated cytotoxicity (ADCC), are essential for γδ T cell-mediated tumor cell killing.

In liver cancer, γδ T cells demonstrate significant cytotoxic activity regulated by cytokines like IL-2 and IL-21. However, the secretion of IL-17 and IL-2 by γδ T cells is associated with poor prognosis due to their role in maintaining and promoting an inflammatory environment. γδ T cells also produce chemokines such as CCR2, CCR5, CCR6, CCR7, and CCR9, which aid in their recruitment and activation.

γδ T cells interact extensively with other immune cells, functioning as antigen-presenting cells (APCs) similar to DCs, and facilitating the activation of CD4+ and CD8+ T cells. They also promote DC maturation via the Fas-Fas L pathway and influence B cell differentiation and antibody production. Additionally, γδ T cells modulate macrophage polarization, contributing to the clearance of infected cells, and regulate neutrophil expansion to alleviate inflammation. However, in the tumor microenvironment, γδ T cells can inhibit αβ T cell activation and support tumor progression.

γδ T cells hold potential for liver cancer immunotherapy, but challenges remain. Their dual role in promoting and inhibiting tumor growth necessitates a nuanced approach to harness their antitumor effects while mitigating their tumor-promoting activities. The increased expression of PD-1 on γδ T cells in liver cancer patients and their interaction with PD-L1+ HCC cells highlight the need for strategies to overcome immune suppression and enhance γδ T cell cytotoxicity.

Understanding the intricate immune regulatory networks involving γδ T cells in liver cancer is crucial for developing effective immunotherapies. Future research should focus on elucidating the mechanisms governing γδ T cell functions and interactions within the TME, paving the way for innovative therapeutic approaches to improve patient outcomes in liver cancer.

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https://www.xiahepublishing.com/2310-8819/JCTH-2023-00355

The study was recently published in the Journal of Clinical and Translational Hepatology.

The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.

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