Characterisation and induction of tissue-resident gamma delta T-cells to target hepatocellular carcinoma

Nekisa Zakeri, Andrew Hall, Leo Swadling, Laura J. Pallett, Nathalie M. Schmidt, Mariana O. Diniz, Stephanie Kucykowicz, Oliver E. Amin, Amir Gander, Massimo Pinzani, Brian R. Davidson, Alberto Quaglia and Mala K. Maini ()
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Nekisa Zakeri: University College London
Andrew Hall: Royal Free London NHS Foundation Trust
Leo Swadling: University College London
Laura J. Pallett: University College London
Nathalie M. Schmidt: University College London
Mariana O. Diniz: University College London
Stephanie Kucykowicz: University College London
Oliver E. Amin: University College London
Amir Gander: University College London
Massimo Pinzani: Royal Free London NHS Foundation Trust
Brian R. Davidson: University College London
Alberto Quaglia: Royal Free London NHS Foundation Trust and UCL Cancer Institute
Mala K. Maini: University College London

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Immunotherapy is now the standard of care for advanced hepatocellular carcinoma (HCC), yet many patients fail to respond. A major unmet goal is the boosting of T-cells with both strong HCC reactivity and the protective advantages of tissue-resident memory T-cells (TRM). Here, we show that higher intratumoural frequencies of γδ T-cells, which have potential for HLA-unrestricted tumour reactivity, associate with enhanced HCC patient survival. We demonstrate that γδ T-cells exhibit bona fide tissue-residency in human liver and HCC, with γδTRM showing no egress from hepatic vasculature, persistence for >10 years and superior anti-tumour cytokine production. The Vγ9Vδ2 T-cell subset is selectively depleted in HCC but can efficiently target HCC cell lines sensitised to accumulate isopentenyl-pyrophosphate by the aminobisphosphonate Zoledronic acid. Aminobisphosphonate-based expansion of peripheral Vγ9Vδ2 T-cells recapitulates a TRM phenotype and boosts cytotoxic potential. Thus, our data suggest more universally effective HCC immunotherapy may be achieved by combining aminobisphosphonates to induce Vγ9Vδ2TRM capable of replenishing the depleted pool, with additional intratumoural delivery to sensitise HCC to Vγ9Vδ2TRM-based targeting.

Date: 2022
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DOI: 10.1038/s41467-022-29012-1

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