Blockade of PD-1/PD-L1 promotes adoptive T-Cell immunotherapy in a tolerogenic environment

Blake, Stephen J. P., Ching, Alan L. H., Kenna, Tony J., Galea, Ryan, Large, Justin, Yagita, Hideo, & Steptoe, Raymond J. (2015) Blockade of PD-1/PD-L1 promotes adoptive T-Cell immunotherapy in a tolerogenic environment. PLoS ONE, 10(3), pp. 1-21.

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Abstract

Adoptive cellular immunotherapy using in vitro expanded CD8+ T cells shows promise for tumour immunotherapy but is limited by eventual loss of function of the transferred T cells through factors that likely include inactivation by tolerogenic dendritic cells (DC). The coinhibitory receptor programmed death-1 (PD-1), in addition to controlling T-cell responsiveness at effector sites in malignancies and chronic viral diseases is an important modulator of dendritic cell-induced tolerance in naive T cell populations. The most potent therapeutic capacity amongst CD8+ T cells appears to lie within Tcm or Tcm-like cells but memory T cells express elevated levels of PD-1. Based on established trafficking patterns for Tcm it is likely Tcm-like cells interact with lymphoid-tissue DC that present tumour-derived antigens and may be inherently tolerogenic to develop therapeutic effector function. As little is understood of the effect of PD-1/PD-L1 blockade on Tcm-like CD8+ T cells, particularly in relation to inactivation by DC, we explored the effects of PD-1/PD-L1 blockade in a mouse model where resting DC tolerise effector and memory CD8+ T cells. Blockade of PD-1/PDL1 promoted effector differentiation of adoptively-transferred Tcm-phenotype cells interacting with tolerising DC. In tumour-bearing mice with tolerising DC, effector activity was increased in both lymphoid tissues and the tumour-site and anti-tumour activity was promoted. Our findings suggest PD-1/PD-L1 blockade may be a useful adjunct for adoptive immunotherapy by promoting effector differentiation in the host of transferred Tcmlike cells. © 2015 Blake et al.

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8 citations in Web of Science®
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ID Code: 94047
Item Type: Journal Article
Refereed: Yes
Keywords: programmed death 1 ligand 1, programmed death 1 receptor, tumor antigen, adoptive immunotherapy, animal cell, animal experiment, animal model, animal tissue, Article, cancer immunotherapy, CD8+ T lymphocyte, cell expansion, cell interaction, cell transport, cellular immunity, chronic disease, controlled study, dendritic cell, effector cell, female, immunological tolerance, in vitro study, lymphocyte differentiation, lymphoid tissue, male, memory T lymphocyte, mouse, mouse model, nonhuman, virus infection, Mus
DOI: 10.1371/journal.pone.0119483
ISSN: 1932-6203
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2015 Blake et al.
Deposited On: 22 Mar 2016 23:32
Last Modified: 23 Mar 2016 21:12

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