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

PLoS One. 2015 Mar 5;10(3):e0119483. doi: 10.1371/journal.pone.0119483. eCollection 2015.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / immunology*
  • Female
  • Immunotherapy, Adoptive*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Programmed Cell Death 1 Receptor / immunology*
  • T-Lymphocytes / immunology*

Substances

  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Programmed Cell Death 1 Receptor

Grant support

Funding was provided by the National Health and Medical Research Council (http://www.nhmrc.gov.au/) Project Grants (631402, GNT1013066) and an Australian Research Council (http://www.arc.gov.au/) ARC Future Fellowship (FT110100372). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.