PD-1 Expression in Pre-Treatment Follicular Lymphoma Predicts the Risk of Subsequent High-Grade Transformation

Enemark, Marie Beck; Monrad, Ida; Madsen, Charlotte Bernhard; Lauridsen, Kristina Lystlund; Honoré, Bent; Plesner, Trine Lindhardt; Hamilton-Dutoit, Stephen; d’Amore, Francesco; Ludvigsen, Maja

doi:10.2147/ott.s289337

Cited by 14 publications

(24 citation statements)

References 33 publications

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“…A clinical study of 121 DLBCL patients showed that immune chemo-therapy lowered the levels of soluble PD-1 (sPD-1), and high pretreatment PD-1 levels were associated with poor clinical outcomes. PD-1 is a predictor of the histological transformation (HT) of FL to DLBCL [39][40][41][42][43]. In primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL), the PD-1/PD-L1 signaling pathway plays an important role in the immune microenvironment, which correlates with increased sensitivity to chemotherapy and OS.…”

Section: Pd-l1 Cancer Cells Utilize the Programmed Cell Death 1/programmed Cell Death Ligand 1 (Pd-1/pd-l1) Pathway To Suppress Immune Cementioning

confidence: 99%

Therapy Strategy of CD47 in Diffuse Large B-Cell Lymphoma (DLBCL)

Zhang

Fan

et al. 2021

Disease Markers

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At present, the use of the common chemotherapy regimen CHOP/R-CHOP for diffuse large B-cell lymphoma (DLBCL) has some shortcomings, especially for relapsed and refractory DLBCL. CD47 is now considered as a prominent target in cancer therapies, and CD47 blockade mainly inhibits the CD47-SIRPα axis to prevent tumor immune escape. Here, we evaluated the effects of the latest CD47 antibodies reported and the correlations of closely related genes with CD47 in this disease. In the future, therapeutic strategies for DLBCL will focus on multitarget antibody combined treatment and multigene joint attacks.

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Section: Pd-l1 Cancer Cells Utilize the Programmed Cell Death 1/programmed Cell Death Ligand 1 (Pd-1/pd-l1) Pathway To Suppress Immune Cementioning

confidence: 99%

Therapy Strategy of CD47 in Diffuse Large B-Cell Lymphoma (DLBCL)

Zhang

Fan

et al. 2021

Disease Markers

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“…A detailed description is given in the Supplementary methods. Immunohistochemical staining was quantified by digital image analysis, and area fractions (AFs), which are defined as the stained area of each tissue section normalized to the area of interest, were compared between MPN-lymphoma and reference samples [ 18 , 25 , 26 , 27 ]. Expression levels of IDH2 protein were based on AFs of strong and intermediate intensity staining, and expression levels of DNAJA2 protein, citrate synthase, lactotransferrin, and myeloblastin were based on AFs of all positive staining.…”

Section: Methodsmentioning

confidence: 99%

Proteomic Profiling Differentiates Lymphoma Patients with and without Concurrent Myeloproliferative Neoplasia

Holst

Enemark

Pedersen

et al. 2021

Cancers

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Myeloproliferative neoplasia (MPN) and lymphoma are regarded as distinct diseases with different pathogeneses. However, patients that are diagnosed with both malignancies occur more frequently in the population than expected. This has led to the hypothesis that the two malignancies may, in some cases, be pathogenetically related. Using a mass spectrometry-based proteomic approach, we show that pre-treatment lymphoma samples from patients with both MPN and lymphoma, either angioimmunoblastic T-cell lymphoma (MPN-AITL) or diffuse large B-cell lymphoma (MPN-DLBCL), show differences in protein expression compared with reference AITL or DLBCL samples from patients without MPN. A distinct clustering of samples from patients with and without MPN was evident for both AITL and DLBCL. Regarding MPN-AITL, a pathway analysis revealed disturbances of cellular respiration as well as oxidative metabolism, and an immunohistochemical evaluation further demonstrated the differential expression of citrate synthase and DNAJA2 protein (p = 0.007 and p = 0.015). Interestingly, IDH2 protein also showed differential expression in the MPN-AITL patients, which contributes to the growing evidence of this protein’s role in both myeloid neoplasia and AITL. In MPN-DLBCL, the disturbed pathways included a significant downregulation of protein synthesis as well as a perturbation of signal transduction. These results imply an underlying disturbance of tumor molecular biology, and in turn an alternative pathogenesis for tumors in these patients with both myeloid and lymphoid malignancies.

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“…PD-1 expression is detected in the TME of 39.5-68.6% of DLBCL cases (Song et al, 2019), but it has mixed clinical implications. While some studies observed that PD-1 + tumor-infiltrating lymphocytes (TILs) are associated with favorable clinical outcome in DLBCL (Muenst et al, 2010;Ahearne et al, 2014;Kiyasu et al, 2015;Fang et al, 2017), a recent study by Enemark et al showed that PD-1 on intrafollicular T cell is a predictive biomarker for histological transformation of FL into DLBCL (Beck Enemark et al, 2021). In DLBCL, PD1 + TIM3 + CD8 + T cells with an effector memory phenotype are observed inside CD20 + B-cell clusters (Roussel et al, 2021).…”

Section: Aberrant Immune Co-stimulation and Co-inhibitionmentioning

confidence: 99%

Epigenetic, Metabolic, and Immune Crosstalk in Germinal-Center-Derived B-Cell Lymphomas: Unveiling New Vulnerabilities for Rational Combination Therapies

Serganova

Chakraborty

Yamshon

et al. 2022

Front. Cell Dev. Biol.

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B-cell non-Hodgkin lymphomas (B-NHLs) are highly heterogenous by genetic, phenotypic, and clinical appearance. Next-generation sequencing technologies and multi-dimensional data analyses have further refined the way these diseases can be more precisely classified by specific genomic, epigenomic, and transcriptomic characteristics. The molecular and genetic heterogeneity of B-NHLs may contribute to the poor outcome of some of these diseases, suggesting that more personalized precision-medicine approaches are needed for improved therapeutic efficacy. The germinal center (GC) B-cell like diffuse large B-cell lymphomas (GCB-DLBCLs) and follicular lymphomas (FLs) share specific epigenetic programs. These diseases often remain difficult to treat and surprisingly do not respond advanced immunotherapies, despite arising in secondary lymphoid organs at sites of antigen recognition. Epigenetic dysregulation is a hallmark of GCB-DLBCLs and FLs, with gain-of-function (GOF) mutations in the histone methyltransferase EZH2, loss-of-function (LOF) mutations in histone acetyl transferases CREBBP and EP300, and the histone methyltransferase KMT2D representing the most prevalent genetic lesions driving these diseases. These mutations have the common effect to disrupt the interactions between lymphoma cells and the immune microenvironment, via decreased antigen presentation and responsiveness to IFN-γ and CD40 signaling pathways. This indicates that immune evasion is a key step in GC B-cell lymphomagenesis. EZH2 inhibitors are now approved for the treatment of FL and selective HDAC3 inhibitors counteracting the effects of CREBBP LOF mutations are under development. These treatments can help restore the immune control of GCB lymphomas, and may represent optimal candidate agents for more effective combination with immunotherapies. Here, we review recent progress in understanding the impact of mutant chromatin modifiers on immune evasion in GCB lymphomas. We provide new insights on how the epigenetic program of these diseases may be regulated at the level of metabolism, discussing the role of metabolic intermediates as cofactors of epigenetic enzymes. In addition, lymphoma metabolic adaptation can negatively influence the immune microenvironment, further contributing to the development of immune cold tumors, poorly infiltrated by effector immune cells. Based on these findings, we discuss relevant candidate epigenetic/metabolic/immune targets for rational combination therapies to investigate as more effective precision-medicine approaches for GCB lymphomas.

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PD-1 Expression in Pre-Treatment Follicular Lymphoma Predicts the Risk of Subsequent High-Grade Transformation

Cited by 14 publications

References 33 publications

Therapy Strategy of CD47 in Diffuse Large B-Cell Lymphoma (DLBCL)

Therapy Strategy of CD47 in Diffuse Large B-Cell Lymphoma (DLBCL)

Proteomic Profiling Differentiates Lymphoma Patients with and without Concurrent Myeloproliferative Neoplasia

Epigenetic, Metabolic, and Immune Crosstalk in Germinal-Center-Derived B-Cell Lymphomas: Unveiling New Vulnerabilities for Rational Combination Therapies

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