Differential effects of PD-L1 versus PD-1 blockade on myeloid inflammation in human cancer
Differential effects of PD-L1 versus PD-1 blockade on myeloid inflammation in human cancer
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DOI：
10.1172/jci.insight.129353
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发表时间：
2020-06-18
期刊：
影响因子：
8
通讯作者：
Dhodapkar, Madhav V.
中科院分区：
文献类型：
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作者：
Bar, Noffar;Costa, Federica;Dhodapkar, Madhav V.
背景PD-1和PD-L1在临床上可互换地作为检查点进行研究，以重振不同肿瘤类型中的T细胞。检查点阻断在人类癌前病变中的生物学效应数据有限。我们在atezolizumab治疗无症状多发性骨髓瘤（AMM）（临床恶性肿瘤的前兆）患者的临床试验中分析了PD-L1阻断的免疫学效应。还将体内纯化的单核细胞和T细胞中PD-L1阻断的基因组特征与肺癌患者中PD-1阻断后的基因组特征进行了比较。分析PD-L1阻断对单核细胞来源的DC的影响，以更好地了解其对髓样抗原呈递细胞的影响。与抗PD-1治疗相反，抗PD-L1治疗导致CD 14+单核细胞中的独特炎症特征和骨髓来源的细胞因子（例如，IL-18）。atezolizumab治疗AMM患者导致循环髓样细胞快速活化和扩增，并持续存在于BM中。PD-L1对纯化的单核细胞来源的DC的阻断导致炎性小体的快速激活，并与CD 40 L驱动的DC成熟协同作用，导致更大的抗原特异性T细胞扩增。这些数据表明，与体内PD-1阻断相比，PD-L1阻断在人体中导致不同的全身免疫效应，特别是表现为快速骨髓活化。这些发现还表明PD-L1作为调节髓系细胞的炎性表型和DC中抗原呈递的检查点的额外作用，这可以用于改善基于PD-L1的联合疗法。
BACKGROUND. PD-1 and PD-L1 have been studied interchangeably in the clinic as checkpoints to reinvigorate T cells in diverse tumor types. Data for biologic effects of checkpoint blockade in human premalignancy are limited.METHODS. We analyzed the immunologic effects of PD-L1 blockade in a clinical trial of atezolizumab in patients with asymptomatic multiple myeloma (AMM), a precursor to clinical malignancy. Genomic signatures of PD-L1 blockade in purified monocytes and T cells in vivo were also compared with those following PD-1 blockade in lung cancer patients. Effects of PD-L1 blockade on monocyte-derived DCs were analyzed to better understand its effects on myeloid antigenpresenting cells.RESULTS. In contrast to anti-PD-1 therapy, anti-PD-L1 therapy led to a distinct inflammatory signature in CD14+ monocytes and increase in myeloid-derived cytokines (e.g., IL-18) in vivo. Treatment of AMM patients with atezolizumab led to rapid activation and expansion of circulating myeloid cells, which persisted in the BM. Blockade of PD-L1 on purified monocyte-derived DCs led to rapid inflammasome activation and synergized with CD40L-driven DC maturation, leading to greater antigen-specific T cell expansion.CONCLUSION. These data show that PD-L1 blockade leads to distinct systemic immunologic effects compared with PD-1 blockade in vivo in humans, particularly manifest as rapid myeloid activation. These findings also suggest an additional role for PD-L1 as a checkpoint for regulating inflammatory phenotype of myeloid cells and antigen presentation in DCs, which may be harnessed to improve PD-L1-based combination therapies.