A New Approach to Enhance the Anti-cancer Function of γδ T Cells

In a recent article published in Nature, researchers identified pathways regulating γδ T-cell killing and BTN3A cell expression by integrating genome-wide CRISPR screening and tumor organoid culture, deepening the understanding of γδ T-cell stress surveillance and suggesting a new pathway to enhance the anticancer function of γδ T cells.

Tumor-associated γδ TCR Variants

Unlike αβ T cells, γδ T cells do not rely on traditional HLA interactions in recognizing infections and tumors, but instead focus on widespread cellular changes. This unique ability links rapid innate immune detection with persistent immune memory, seamlessly integrating the dual properties of innate and adaptive immunity. Given their potential responsiveness to tumors, elucidation of novel tumor-associated γδ TCR variants is critical for accurate targeting of tumor-associated antigens.

• Vγ9Vδ2-positive T cells are a subpopulation of γδ T cells that uniquely recognize phospho-antigens and are critical for tumor surveillance and pathogen response.
• Vγ9Vδ2-negative T cells exhibit tissue-specific residency and contribute to a variety of immune functions including wound healing and tissue regeneration.

An in-depth understanding of the various structural domains of the Vγ9Vδ2 TCR, as well as interactions with ligands and epigenetic modifiers, is necessary, as well as a deeper understanding of the interactions between subpopulations of γδ T cells and their transformed target cells.

Regulatory Pathways of γδ T Cell-Cancer Cell Interactions

Vγ9Vδ2 T cells, which represent the most predominant subpopulation of human γδ T cells, recognize a protein complex containing butyrate-binding protein 2A1 (BTN2A1) and BTN3A1.

• BTN2A1-3A1-3A2 surface complex is activated upon intracellular phosphor-antigen binding from the acetate pathway to BTN3A1, allowing BTN2A1 to bind to the Vγ9Vδ2 TCR.
• Regulation of BTN2A1 and BTN3A surface expression is influenced by cellular metabolic pathways. This regulation signals to the Vγ9Vδ2 T cells about changes or stress in the target cells.
• Moreover, their presence has been documented in various other tissues, including the lungs, where they are implicated in both protective and pathogenic responses.
• The mechanism by which AMP-activated protein kinase (AMPK) regulates BTN2A1 and BTN3A expression in energetically stressed cells reveals a key stress-regulated pathway for the interaction between γδ T cells and cancer cells. Activation of AMPK enhances the sensitivity of these cells to the cytotoxic effects of T cells expressing the Vγ9Vδ2 TCR.

These insights shed light on γδ T cell-based anti-cancer therapeutic approaches.

Fig. 1 Vγ9Vδ2 TCR-mediated killing of cancer cells.¹

γδ T Cells-based Anti-cancer Therapies

Traditionally, the exploitation of γδ T cells in cancer immunotherapy has involved their in vivo expansion via the administration of phosphor-antigens or amino bisphosphonates, such as Zoledronic acid, which activate the Vγ9Vδ2 subset of γδ T cells. However, activated γδ T cells are not persistent in vivo.

To overcome these obstacles, we can take advantage of new pathways discovered by research to genetically manipulate γδ T cells to enhance their inherent anti-tumor functions.

• CAR-γδ T cells
• TCR engineering
• Combination strategies

Creative Biolabs, given its relentless commitment towards illuminating novel therapeutic potentials, continues to deliver unparalleled expertise and cutting-edge technologies to facilitate the development of γδ T cell-based treatments for cancer.

Reference

1. Zhou Jian, et al. "Decoding γδ T cell anticancer therapies: integrating CRISPR screens with tumor organoids." Signal Transduction and Targeted Therapy 8.1 (2023): 423.