Blockade of PD-1/PD-L1 promotes adoptive T-cell immunotherapy in a tolerogenic environment.
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 co-inhibitory 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/PD-L1 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 Tcm-like cells.
UQ Diamantina Institute, University of Queensland, Brisbane, Australia.
Stephen J P
SJ
Blake
UQ Diamantina Institute, University of Queensland, Brisbane, Australia.
Alan L H
AL
Ching
UQ Diamantina Institute, University of Queensland, Brisbane, Australia.
Tony J
TJ
Kenna
UQ Diamantina Institute, University of Queensland, Brisbane, Australia.
Ryan
R
Galea
UQ Diamantina Institute, University of Queensland, Brisbane, Australia.
Justin
J
Large
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
Hideo
H
Yagita
UQ Diamantina Institute, University of Queensland, Brisbane, Australia.
Raymond J
RJ
Steptoe
D000818:Animals; D060890:B7-H1 Antigen / Q000276:immunology*; D005260:Female; D016219:Immunotherapy, Adoptive; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D061026:Programmed Cell Death 1 Receptor