PD-L1 gene alterations identify a subset of diffuse large B-cell lymphoma harboring a T-cell-inflamed phenotype
PD-L1 gene alterations identify a subset of diffuse large B-cell lymphoma harboring a T-cell-inflamed phenotype
复制标题
DOI：
10.1182/blood-2018-10-879015
复制
发表时间：
2019-05-23
期刊：
影响因子：
20.3
通讯作者：
Kline, Justin
中科院分区：
文献类型：
--
作者：
Godfrey, James;Tumuluru, Sravya;Kline, Justin
程序性死亡配体1 （PD-L1）在恶性细胞上的表达是多种人类癌症的主要免疫逃逸机制。在经典霍奇金淋巴瘤（cHL）中发现了PD-L1上调的独特遗传机制，其中包含程序性死亡-1 （PD-1）配体PD-L1和PD-L2的染色体区域（9p24.1）的拷贝增益反复观察到。虽然染色体9p24.1拷贝数改变在cHL中普遍存在，但它们也发生在弥漫性大b细胞淋巴瘤（DLBCL）中，尽管发病率较低。在这里，荧光原位杂交被用来鉴定含有PD-L1基因改变的dlbcl，从而能够表征这些淋巴瘤的免疫基因组景观。在分析的105例DLBCL病例中，27%发现PD-L1改变。PD-L1的改变在非生发中心的dlbcl中高度富集，并表现出强大的PD-L1蛋白表达。这些淋巴瘤被克隆限制性T细胞严重浸润，并且经常下调人白细胞抗原的表达。pd - l1改变的dlbcl的RNA测序显示，参与负t细胞调控和NF-kB通路激活的基因上调，而全外显子组测序发现，参与抗原呈递和t细胞共刺激的基因频繁突变。这些发现中的许多都在一个大型的外部数据集中得到了验证。有趣的是，PD-L1改变的DLBCL患者在一线化疗免疫治疗后无进展生存期较差；然而，在复发/难治性环境中，PD-L1的改变与抗pd -1治疗的反应相关。总的来说，我们的研究结果表明，PD-L1的改变确定了DLBCL的一个独特的生物学亚群，其中内源性抗淋巴瘤免疫反应已被激活，并且与PD-1阻断治疗的反应性相关。
Programmed death-ligand 1 (PD-L1) expression on malignant cells is a dominant immune escape mechanism across a variety of human cancers. A unique genetic mechanism underlying PD-L1 upregulation has been uncovered in classical Hodgkin lymphoma (cHL), in which copy gains of the chromosomal region (9p24.1) containing the programmed death-1 (PD-1) ligands PD-L1 and PD-L2 are recurrently observed. While chromosome 9p24.1 copynumber alterations are ubiquitous in cHL, they also occur in diffuse large B-cell lymphoma (DLBCL), albeit with a lower incidence. Here, fluorescence in situ hybridization was used to identify DLBCLs harboring PD-L1 gene alterations, thereby enabling a characterization of the immunogenomic landscape of these lymphomas. Among 105 DLBCL cases analyzed, PD-L1 alterations were identified in 27%. PD-L1 alterations were highly enriched among non-germinal center DLBCLs and exhibited robust PD-L1 protein expression. These lymphomas were heavily infiltrated by clonally restricted T cells and frequently downregulated human leukocyte antigen expression. RNA sequencing of PD-L1-altered DLBCLs revealed upregulation of genes involved in negative T-cell regulation and NF-kB pathway activation, while whole-exome sequencing identified frequent mutations in genes involved in antigen presentation and T-cell costimulation. Many of these findings were validated in a large external data set. Interestingly, DLBCL patients with PD-L1 alterations had inferior progression-free survival following front-line chemoimmunotherapy; however, in the relapsed/refractory setting, PD-L1 alterations were associated with response to anti-PD-1 therapy. Collectively, our results indicate that PD-L1 alterations identify a unique biological subset of DLBCL in which an endogenous antilymphoma immune response has been activated, and that is associated with responsiveness to PD-1 blockade therapy.