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PD-L1 gene alterations identify a subset of diffuse large B-cell lymphoma harboring a T cell-inflamed phenotype.

著者 Godfrey J , Tumuluru S , Bao R , Leukam M , Venkataraman G , Phillip J , Fitzpatrick C , McElherne J , MacNabb BW , Orlowski R , Smith SM , Kline J
Blood.2019 Mar 25 ; ():.
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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 up-regulation has been uncovered in classical Hodgkin lymphoma (cHL), in which copy gains of the chromosomal region (9p24.1) containing the PD-1 ligands (PD-L1 and PD-L2) are recurrently observed. While chromosome 9p24.1 copy number alterations are ubiquitous in cHL, they also occur in diffuse large B-cell lymphoma (DLBCL), albeit with a lower incidence. Here, FISH was utilized 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 down-regulated human leukocyte antigen expression. RNA-sequencing of PD-L1 altered DLBCLs revealed up-regulation of genes involved in negative T cell regulation and NF-κB pathway activation, while whole exome sequencing identified frequent mutations in genes involved in antigen presentation and T cell co-stimulation. Many of these findings were validated in a large external dataset. Interestingly, DLBCL patients with PD-L1 alterations had inferior progression-free survival following front-line chemo-immunotherapy, 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 anti-lymphoma immune response has been activated, and which is associated with responsiveness to PD-1 blockade therapy.
PMID: 30910787 [PubMed - as supplied by publisher]
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