Blockade of PD-1/PD-L1 Promotes Adoptive T-Cell Immunotherapy in a Tolerogenic Environment

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.

Antigen presenting cell‐targeted proinsulin expression converts insulin‐specific CD8+ T‐cell priming to tolerance in autoimmune‐prone NOD mice

“…From this it might be predicted that administration of anti-PD-1 antibodies would reverse unresponsiveness as reported in a similar setting by others [41]. However, in a similar model of tolerance induction by enforced antigen expression, PD-1 blockade more effectively promoted development of effector function during tolerance induction than reversal of unresponsiveness [42]. Extending this, it remains unclear whether precipitation of T1D by PD-1/PD-L1 blockade in humans [43] results either from reversal of tolerance or from promotion of effector function in spontaneously-activated islet-specific T cells, but this warrants clarification.…”

Single segment of spleen autotransplantation, after splenectomy for trauma, can restore splenic functions

“…T lymphocytes in the tumor environment are often PD-1 positive and are defined as exhausted lymphocytes, indicating a poor responsive status of T cells, with decreased production of effective cytokines and a lack of cytotoxic activity [27]. In fact, targeting the PD-1 immune checkpoint has shown significant clinical efficacy in the treatment of many advanced cancers resistant to conventional chemotherapy [28].…”

Immune Checkpoint Inhibitors as First-Line and Salvage Therapy for Advanced Non-Small-Cell Lung Cancer

“…The PD-1/PD-L1 interaction may also be more important in mediating T-cell exhaustion, as blockade of this pathway -unlike blockade of the CTLA-4 pathway -has been shown to restore CD8 + T-cell function in chronic viral infection [27] and more recently in cancer [28].…”