Overcoming constraints on gamma delta T-cell immunotherapy for hepatocellular carcinoma

More effective immunotherapies are urgently needed for hepatocellular carcinoma (HCC). In previous work, I demonstrated for the first time the therapeutic potential of gamma-delta (ɣδ)T-cells for HCC. I showed that ɣδT-cells exhibit a tissue-resident memory(TRM) phenotype in human liver and HCC, with superior anti-tumour function. However a major subset, Vɣ9Vδ2T-cells, were selectively depleted in HCC, which correlated with poorer prognosis. I subsequently demonstrated that a de-novo TRM phenotype can be recapitulated on expanded blood Vɣ9Vδ2T-cells for adoptive cell-transfer, and combined with intratumoural delivery of the aminobisphosphonate Zoledronate, to enhance Vɣ9Vδ2TRM-mediated lysis of HCC cell-lines (Zakeriet.al.Nat Comm.2022).

In this project, I will study for the first time the mechanisms of Vɣ9Vδ2T-cell recruitment across HCC endothelium and assess whether an induced TRM phenotype can confer improved tissue-retention and tumour-migration properties. I will utilise 3D preclinical models of HCC to examine whether intratumoural Zoledronate can enhance the local activation and anti-tumour function of Vɣ9Vδ2TRM, whist minimising off-target effects. Furthermore, I will explore whether synergistic immune checkpoint blockade can further amplify Vɣ9Vδ2TRM anti-HCC responses.

This work will provide critical insights to inform a future trial comprising Vɣ9Vδ2T-cell immunotherapy alongside targeted drug delivery, with the goal of developing a more universally effective immunotherapy for HCC.