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L-selectin enhanced T cells improve the efficacy of cancer immunotherapy

Watson, H. Angharad, Durairaj, R. R. P., Ohme, Julia, Alatsatianos, Markella, Almutairi, Hanan, Mohammed, R. N., Vigar, Miriam, Reed, Sophie G., Paisey, Stephen J., Marshall, Christopher, Gallimore, Awen and Ager, Ann 2019. L-selectin enhanced T cells improve the efficacy of cancer immunotherapy. Frontiers in Immunology 10 , 1321. 10.3389/fimmu.2019.01321

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Abstract

The T cell homing molecule, L-selectin (CD62L), is commonly used as a marker of T cell activation, as expression of L-selectin is downregulated following engagement of the T cell receptor. Furthermore, it is used to distinguish “central memory” T cells (TCM) from, “effector memory” T cells (TEM). It has been reported that CD8+ T cells with a CD62L+ TCM phenotype are better able to control tumour growth than CD62L- TEM CD8+ T cells, while L-selectin knockout T cells are poor at controlling tumour growth. Here, we test the hypothesis that T cells expressing a genetically modified form of L-selectin that is not downregulated following T cell activation (L-selectin enhanced T cells) are better able to control tumour growth than wild type T cells. Using mouse models of solid and disseminated tumours, we show that L-selectin enhancement improves the efficacy of CD8+ T cells in controlling tumour growth. Longitudinal tracking of Zirconium-89 (89Zr) labelled T cells using PET-CT showed that transferred T cells localised to tumours within 24 hours. Early T cell recruitment into tumours was not dependent on L-selectin, however, upregulation of the early activation marker CD69 was higher on L-selectin expressing T cells both inside tumours and in secondary lymphoid organs. Reduced growth of tumours by L-selectin enhanced T cells correlated with increased frequency of CD8+ tumour infiltrating T cells 21 days after commencing therapy. Ex vivo analysis showed that clonal expansion of L-selectin enhanced T cells was slower, and that L-selectin was linked to expression of the proliferation marker Ki67. Together these findings indicate that maintaining L-selectin expression on tumour-specific T cells offers an advantage in mouse models of cancer immunotherapy. The beneficial role of L-selectin may be unrelated to its’ well-known role in T cell homing and instead linked to activation, clonal expansion and retention of therapeutic T cells. These findings have implications both for the selection of T cell subsets for adoptive transfer immunotherapy, and for possible modifications of transgenic chimeric antigen receptor (CAR) T cells to broaden the clinical scope of these therapies.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Wales Research Diagnostic Pet Imaging Centre (PETIC)
Systems Immunity Research Institute (SIURI)
Publisher: Frontiers Media
ISSN: 1664-3224
Funders: MRC, Wellcome Trust
Date of First Compliant Deposit: 29 May 2019
Date of Acceptance: 24 May 2019
Last Modified: 11 Sep 2019 07:45
URI: http://orca-mwe.cf.ac.uk/id/eprint/122938

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