Role of Tissue-resident γδ T Cells in Hepatocellular Carcinoma

γδ T cells play a key role in tumor immune surveillance and are not restricted by MHC in antigen recognition. The major human γδ T cell subtypes are Vδ1 and Vδ2 T cells, both of which recognize stress-inducing molecules, including MHC-1-like chain-associated proteins A/B and UL16-binding proteins.

Some studies have found that γδ T cells are associated with hepatocellular carcinoma, show tissue residency in the liver, and exhibit a high capacity for cytokine production.

Vδ1 and Vδ2 T cells with Tissue-resident Phenotype in Human Liver

Tissue-resident memory T cells (TRM) are phenotypically and functionally unique sentinels in the liver that can be retained for long periods of time and are well positioned for rapid and effective first-line immunosurveillance with the marker molecules CD69, CD103, and CD49a.

Some investigators have studied whether Vδ1 and Vγ9Vδ2 T cells reside in the liver by TRM marker molecules. The results showed that subpopulations of Vδ1 and Vγ9Vδ2 T cells isolated from the liver expressed TRM signature markers.

• These tissue-resident γδ T cell subpopulations consisted predominantly of CD27 ^- CD45RA ^- effector memory cells composed of distinct CD69 ⁺ CD103 ⁺ or CD69 ⁺ CD49a ⁺ subpopulations.
• In addition, there was increased expression of the Vδ1 and Vγ9Vδ2 T cell chemokine receptors CXCR6 and CXCR3.

Vδ1 and Vγ9Vδ2 TRM cells reside in liver tissue for a long time. γδ T cells infiltrating into the liver from the peripheral circulation are able to partially acquire a TRM phenotype to complement intrahepatic γδ TRM cells.

Functional Characterization of Hepatic γδ TRMs

Further evaluation of hepatic γδ TRM is important for immunotherapy.

• Vδ1 and Vγ9Vδ2 TRM express higher levels of the T cell activation marker HLA-DR, but show significantly lower cytotoxic potential.
• Vδ1 and Vγ9Vδ2 TRM produced the pro-survival cytokine IL-2 more rapidly than non-TRM cells.
• Most Vδ1 and Vγ9Vδ2 TRM also rapidly produced the anti-tumor cytokine IFN-γ after stimulation.
• Compared to non-TRM cells in vitro, Vδ1 and Vγ9Vδ2 TRM expressed higher levels of PD1. Vδ1 and Vγ9Vδ2 T cells with high PD-1 expression maintained their ability to produce IFN-γ after stimulation.

Tissue-resident γδ T Cells in Hepatocellular Carcinoma

• Surveillance and Early Detection
  Tissue-resident γδ T cells residing within the liver parenchyma proactively patrol liver tissue to detect and eliminate cells with early signs of malignant transformation.
• Crosstalk with Other Immune Cells
  Tissue-resident γδ T cells interact dynamically with other immune cells by virtue of their unique antigen recognition capabilities. This collaboration influences the progression or regression of hepatocellular carcinoma.
• Immunosuppressive Microenvironment
  In this context, tissue-resident γδ T cells may face suppression or depletion, thereby impairing their ability to mount an effective anti-tumor response.

As research continues to elucidate the multifaceted role of tissue-resident γδ T cells, the prospect of harnessing their unique ability to deliver precision immunotherapy for hepatocellular carcinoma emerges as a promising frontier in the fight against this dreaded malignancy.

Creative Biolabs remains at the forefront of these efforts and is committed to advancing our knowledge and translating it into effective γδ T cell solutions.

Reference

1. Zakeri, Nekisa, et al. "Characterisation and induction of tissue-resident gamma delta T-cells to target hepatocellular carcinoma." Nature Communications 13.1 (2022): 1372.