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.

采用体外扩增CD8阳性T细胞（CD8+ T cells）的过继细胞免疫治疗在肿瘤免疫治疗领域展现出应用潜力，但输注的T细胞最终会因多种因素出现功能丧失，其中可能包括致耐受性树突状细胞（tolerogenic dendritic cells, DC）介导的失活。共抑制受体程序性死亡受体1（programmed death-1, PD-1）除可调控恶性肿瘤及慢性病毒性疾病中效应位点的T细胞应答外，还是初始T细胞群中树突状细胞介导耐受的重要调节因子。CD8+ T细胞中治疗潜力最强的群体似乎为中枢记忆性T细胞（central memory T cells, Tcm）或类Tcm细胞，但记忆性T细胞高表达PD-1。基于已明确的Tcm归巢模式，类Tcm细胞大概率会与呈递肿瘤源性抗原的淋巴组织DC发生相互作用，且这类细胞可能固有具备致耐受性，以获得治疗性效应功能。目前学界对PD-1/PD-L1阻断对类Tcm型CD8+ T细胞的影响尚缺乏深入了解，尤其是在DC介导其失活的相关场景中，因此我们在静息DC诱导效应性与记忆性CD8+ T细胞耐受的小鼠模型中，探究了PD-1/PD-L1阻断的作用效果。研究结果显示，PD-1/PD-L1阻断可促进过继输注的Tcm表型细胞与正在诱导耐受的DC相互作用后的效应分化。在存在DC诱导耐受的荷瘤小鼠中，淋巴组织与肿瘤部位的效应活性均显著提升，抗肿瘤活性也得到增强。本研究表明，PD-1/PD-L1阻断可通过促进宿主体内输注的类Tcm样细胞的效应分化，成为过继免疫治疗的有效辅助手段。