PD-L1 alterations appeared to identify a subset of patients with diffuse large B-cell lymphoma who have an endogenous anti-lymphoma immune response, according to results of a prospective study published in Blood.
Activation of this response is associated with responsiveness to PD-1 blockade therapy, researchers noted.
“Recently, enthusiasm has grown to incorporate PD-1 blockade immunotherapy for DLBCL due to its tremendous efficacy in classical Hodgkin lymphoma and other aggressive B-cell lymphomas,” Justin Kline, MD, associate professor of medicine at University of Chicago, and colleagues wrote. “However, objective response rates to anti-PD-1 therapy in unselected patients with relapsed/refractory DLBCL is modest. These mixed outcomes likely reflect the heterogeneous nature of DLBCL, as demonstrated by gene expression profiling and large-scale genomic analyses, and suggest that if anti-PD-1 monotherapy is to impact the management of DLBCL, future efforts should be focused on developing predictive biomarkers that accurately identify subsets of patients likely to benefit from this treatment approach.”
Kline and colleagues conducted fluorescence in-situ hybridization (FISH) analysis of 105 DLBCL specimens to identify those that harbored PD-L1 gene alterations.
They excluded primary mediastinal B-cell lymphomas, gray-zone lymphomas and Epstein-Barr virus- or HIV-associated lymphomas from the analysis.
Results showed that 28 cases (27%) had PD-L1 alterations that displayed strong PD-L1 protein expression and were highly enriched among nongerminal center DLBCLs.
Of the specimens, 17 showed relative PD-L1 copy gains, seven had PD-L1 amplifications, two had PD-L1 translocations and two were polysomic for chromosome 9.
Clonally restricted T-cells heavily infiltrated these lymphomas, with frequently downregulated HLA expression.
RNA sequencing on 24 specimens (12 with altered PD-L1 and 12 without altered PD-L1) showed an upregulation of genes associated with negative T-cell regulation and NF-B pathway activation among specimens with altered PD-L1.
Whole exome sequencing revealed recurrent somatic mutations in several genes among PD-L1-altered lymphomas, including TNFAIP3 and TP53, as well as genes critical for immune surveillance, such as B2M, CIITA and HLA. Mutations in genes involved in T-cell co-stimulation, including CD70 and CD83, also appeared more common in the PD-L1-altered DLBCLs.
An analysis of the effect of PD-L1 alterations on DLBCL outcomes after frontline chemoimmunotherapy showed patients with these alterations had inferior PFS after median follow-up of 4.2 years (HR = 2.62; 95% CI, 1.12-6.2).
However, PD-L1 alterations were associated with response to anti-PD-L1 therapy in the relapsed or refractory setting.
“Our results raise new and important questions regarding the immune landscape of DLBCL,” Kline and colleagues wrote. “Based upon our findings, we propose a model in which enhanced lymphoma cell-intrinsic NF-B activation not only drives tumor growth and proliferation, but also creates an inflammatory environment more conducive to the recruitment and activation of adaptive antitumor immune responses, similar to what has been reported with NF-B hyperactivation within the solid tumor microenvironment.” – by John DeRosier
Disclosures: Kline reports a consultant role with and research funding from Merck. Please see the study for all other authors’ relevant financial disclosures.