Targeted Therapies and Immune Checkpoint Inhibitors in Primary CNS Lymphoma

Wirsching, Hans-Georg; Weller, Michael; Balabanov, Stefan; Roth, Patrick

doi:10.3390/cancers13123073

Cited by 17 publications

(9 citation statements)

References 78 publications

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“…The histone lysine methyltransferase, KMT2D , has a higher mutation frequency in PCNSL patients than in de novo DLBCLs [ 21 , 22 ]. ROBO1 is mainly expressed in vascular endothelial cells and is involved in angiogenesis through the Slit-Robo signaling pathway [ 23 ]. In myeloma study, ROBO1 also regulates the cancer microenvironment by inducing cancer cells to homing, disseminating, and surviving [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of Tumor Microenvironment and Angiogenesis on Clinical Outcomes of Primary Central Nervous System Lymphoma

Wang

Hsiao

et al. 2021

BioMed Research International

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Primary central nervous system lymphoma (PCNSL) is a rare lymphoma, and the disease course is often aggressive with poor prognosis outcomes. PCNSL undergoes germinal center reactions and impairs B-cell maturation. However, angiogenesis is also involved in the tumorigenesis and progression of PCNSL. This study investigated the effects of the tumor microenvironment and angiogenesis-associated genomic alterations on the outcomes of PCNSL. The analysis also evaluated the influence of treatment modality and timing on PCNSL survival using partial least squares variance-based path modeling (PLS-PM). PLS-PM can be used to evaluate the complex relationship between prognostic variables and disease outcomes with a small sample of measurements and structural models. A total of 19 immunocompetent PCNSL samples were analyzed by exome sequencing. Our results suggest that the timing of radiotherapy and mutations of ROBO1 and KAT2B are potential indicators of PCNSL outcomes and may be affected by baseline characteristics such as age and sex. Our results also showed that patients with no mutations of ROBO1 and KAT2B, SubRT subgroup showed favorable survival outcomes compared with no SubRT subgroup in short-term follow-up. All SubRT patients have received high-dose methotrexate induction chemotherapy in the initial treatment. Therefore, initial induction chemotherapy combined with subsequent radiotherapy might improve survival outcomes in PCNSL patients who have no ROBO1 and KAT2B somatic mutations in short-term follow-up. The overall findings suggest that the tumor microenvironment and angiogenesis-associated genomic alterations and treatment modalities are potential indicators of overall survival and may be affected by the baseline characteristics of PCNSL patients.

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Section: Discussionmentioning

confidence: 99%

Effect of Tumor Microenvironment and Angiogenesis on Clinical Outcomes of Primary Central Nervous System Lymphoma

Wang

Hsiao

et al. 2021

BioMed Research International

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“…The whole brain radiation therapy (WBRT) in combination with chemotherapeutic agents such as methotrexate is still a more common treatment modality. And some studies ( Wirsching et al, 2021 ) have suggested that isitinib may be a more promising therapeutic agent. As immunotherapy becomes more popular, more immune agents such as PD-1/PD-L1 monoclonal antibodies are being used in oncology treatment.…”

Section: Discussionmentioning

confidence: 99%

Molecular characteristics of immunocytes infiltration in primary central nervous system lymphoma

Zhang

Sun²,

Lu³

et al. 2022

Front. Genet.

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Background: Primary central nervous system lymphoma (PCNSL) is a rare B-cell lymphoma of central nervous system, which is often found in immunocompromised patients. The common clinical treatment of PCNSL is methotrexate (MTX) and whole brain radiation therapy. With the development of tumour immunology research, the tumour microenvironment of PCNSL is characterised by abnormal expression of different immune signature molecules and patients with PCNSL may benefit from tumour immunotherapy.Methods: In our research, RNA-seq data from 82 PCNSL patients were collated by mining the microarray data from the GEO database. All samples were classified into three types related to tumour immune response by the Cibersort algorithm and consistent clustering. Differential analysis of genes was used to uncover 2 sets of differential genes associated with tumour immunity. The ICI scores of each sample were obtained by PCA algorithm, and the relationship between ICI scores and immune checkpoint expression, immunotherapy and drug sensitivity was investigated. Genes associated with ICI scores and their functional characteristics were investigated by WGCNA analysis and PPI analysis, based on the ICI scores of each sample.Results: The tumour microenvironment in PCNSL has a greater relationship with the tumour immune response. ICI scores obtained from 375 differential genes were associated with multiple immune responses in PCNSL. PCNSL patients with higher ICI scores had a better tumour microenvironment and were sensitive to immunotherapy and some small molecule drug. This study also identified 64 genes associated with ICI scores, which may serve as important therapeutic and prognostic targets for PCNSL.Conclusion: The presence of multiple immunosuppressive responses in the tumour microenvironment of PCNSL which suggested that improving the immune function of PCNSL patients through immunotherapy and targeted therapies can be an effective treatment for PCNSL. And the ICI score and associated genes may also provide a better predictor of the clinical use of immunotherapy.

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“…However, the frequency of these gains varies markedly in independent studies, ranging from 21% (4/19) [ 27 ] to 67% (28/42) [ 22 ]. Furthermore, a variable expression of PDL-1/PD-1 protein has been reported, and it remains unknown whether molecular aberrations correlate with the protein level (reviewed by Wirsching et al [ 48 ]). This raises questions regarding the technological approaches and cut-offs used to diagnose these aberrations.…”

Section: Molecular Pathogenesis Of Pcnslmentioning

confidence: 99%

Impact of a Faulty Germinal Center Reaction on the Pathogenesis of Primary Diffuse Large B Cell Lymphoma of the Central Nervous System

Montesinos‐Rongen

Brunn

Sánchez‐Ruiz

et al. 2021

Cancers

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Primary lymphoma of the central nervous system (PCNSL, CNS) is a specific diffuse large B cell lymphoma (DLBCL) entity confined to the CNS. Key to its pathogenesis is a failure of B cell differentiation and a lack of appropriate control at differentiation stages before entrance and within the germinal center (GC). Self-/polyreactive B cells rescued from apoptosis by MYD88 and/or CD79B mutations accumulate a high load of somatic mutations in their rearranged immunoglobulin (IG) genes, with ongoing somatic hypermutation (SHM). Furthermore, the targeting of oncogenes by aberrant SHM (e.g., PIM1, PAX5, RHOH, MYC, BTG2, KLHL14, SUSD2), translocations of the IG and BCL6 genes, and genomic instability (e.g., gains of 18q21; losses of 9p21, 8q12, 6q21) occur in these cells in the course of their malignant transformation. Activated Toll-like receptor, B cell receptor (BCR), and NF-κB signaling pathways foster lymphoma cell proliferation. Hence, tumor cells are arrested in a late B cell differentiation stage, corresponding to late GC exit B cells, which are genetically related to IgM+ memory cells. Paradoxically, the GC reaction increases self-/polyreactivity, yielding increased tumor BCR reactivity for multiple CNS proteins, which likely contributes to CNS tropism of the lymphoma. The loss of MHC class I antigen expression supports tumor cell immune escape. Thus, specific and unique interactions of the tumor cells with resident CNS cells determine the hallmarks of PCNSL.

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Targeted Therapies and Immune Checkpoint Inhibitors in Primary CNS Lymphoma

Cited by 17 publications

References 78 publications

Effect of Tumor Microenvironment and Angiogenesis on Clinical Outcomes of Primary Central Nervous System Lymphoma

Effect of Tumor Microenvironment and Angiogenesis on Clinical Outcomes of Primary Central Nervous System Lymphoma

Molecular characteristics of immunocytes infiltration in primary central nervous system lymphoma

Impact of a Faulty Germinal Center Reaction on the Pathogenesis of Primary Diffuse Large B Cell Lymphoma of the Central Nervous System

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