In the JournalsPerspective

PD-L1 alterations identify T-cell inflamed diffuse large B-cell lymphoma

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.

 

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.

 

    Perspective
    Stephen Ansell

    Stephen Ansell

    This is an interesting study as previous data have shown there is a subset of patients with lymphoma with overexpression of PD-L1 due to amplification or copy number gains. Although this is common in Hodgkin lymphoma, it’s less common in large cell lymphoma, accounting for approximately 10% to 15% of patients. This study confirms the prevalence in large cell lymphomas in a relatively large cohort of patients.

    What’s additionally interesting is that genetic alterations in PD-L1 seem to generate a T-cell inflamed phenotype. There is clearly a population of T cells in these cases that are clonally restricted, suggesting they are trying to target the tumor cells but are being inhibited. The researchers showed that when you block PD-1, those patients seem to benefit from treatment. PD-L1 amplification therefore seems to define a unique biology in large cell lymphoma. PD-L1 alterations seem to have an association with T-cell recruitment and T-cell clonality that appears directed against the tumor, and this subset of patients may benefit from blocking PD-1 signaling.

    It would be very helpful if future studies using PD-1 blocking antibodies specifically required PD-L1 amplifications or alterations as entry criteria. Based on recent trial data, we know that if an unselected group of patients with large cell lymphoma is treated with PD-1 blockade, the response rate is only 10% or less. The response rates may be substantially higher if only large B-cell lymphoma with PD-L1 alterations are included, and this strategy could help us identify large cell lymphoma patients for whom PD-1-blocking antibodies are the most useful.

    • Stephen Ansell, MD, PhD
    • HemOnc Today Editorial Board Member
      Mayo Clinic

    Disclosures: Ansell reports research funding to his institution from Bristol-Myers Squibb and Merck.

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