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

James Godfrey, Sravya Tumuluru, Riyue Bao, Michael Leukam, Girish Venkataraman, John Phillip, Carrie Fitzpatrick, James McElherne, Brendan W. MacNabb, Robert Orlowski, Sonali M. Smith and Justin Kline

Key points

  • PD-L1 gene alterations, identified in ~25% of DLBCL, are characterized by heightened measures of host immune surveillance in this disease.

  • PD-L1 gene alterations are associated with response to PD-1 blockade in DLBCL, making this a promising biomarker for future investigation.

Abstract

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.

  • Submitted October 11, 2018.
  • Accepted March 4, 2019.