The CXCR4-CXCL12-Axis is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects in Vitro

Pansy, Katrin; Feichtinger, Julia; Ehall, Barbara; Uhl, Barbara; Sedej, Miriam; Roula, David; Pursche, Beata; Wolf, Axel; Zoidl, Manuel; Steinbauer, Elisabeth; Gruber, Verena; Greinix, Hildegard; Prochazka, Katharina; Thallinger, Gerhard; Heinemann, Ákos; Beham‐Schmid, Christine; Neumeister, Peter; Wrodnigg, Tanja; Fechter, Karoline; Deutsch, Alexander

doi:10.20944/preprints201907.0352.v1

Cited by 4 publications

(2 citation statements)

References 47 publications

(84 reference statements)

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“… 21 , 22 Whereas gene expression of CD79b, the target of this ADC, is around a median of 7.5 fold-higher in DLBCL patients than non-neoplastic controls, the CXCR4 gene expression, targeted by the T22-AUR nanoconjugate in DLBCL samples is on average 140-fold higher than in normal controls. 10 , 38 Thus, our nanoconjugate can be targeted more specifically due to the huge CXCR4 overexpression existing in DLBCL patients. Our nanoconjugate achieves a potent block of lymphoma dissemination with complete lack of associated toxicity in normal organs.…”

Section: Discussionmentioning

confidence: 99%

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Specific Cytotoxic Effect of an Auristatin Nanoconjugate Towards CXCR4+ Diffuse Large B-Cell Lymphoma Cells

Falgàs

Pallarès

Unzueta

et al. 2021

IJN

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Background and Purpose Around 40–50% of diffuse large-B cell lymphoma (DLBCL) patients suffer from refractory disease or relapse after R-CHOP first-line treatment. Many ongoing clinical trials for DLBCL patients involve microtubule targeting agents (MTAs), however, their anticancer activity is limited by severe side effects. Therefore, we chose to improve the therapeutic window of the MTA monomethyl auristatin E developing a nanoconjugate, T22-AUR, that selectively targets the CXCR4 receptor, which is overexpressed in many DLBCL cells (CXCR4 + ) and associated with poor prognosis. Methods The T22-AUR specificity towards CXCR4 receptor was performed by flow cytometry in different DLBCL cell lines and running biodistribution assays in a subcutaneous mouse model bearing CXCR4 + DLBCL cells. Moreover, we determined T22-AUR cytotoxicity using cell viability assays, cell cycle analysis, DAPI staining and immunohistochemistry. Finally, the T22-AUR antineoplastic effect was evaluated in vivo in an extranodal CXCR4 + DLBCL mouse model whereas the toxicity analysis was assessed by histopathology in non-infiltrated mouse organs and by in vitro cytotoxic assays in human PBMCs. Results We demonstrate that the T22-AUR nanoconjugate displays CXCR4-dependent targeting and internalization in CXCR4 + DLBCL cells in vitro as well as in a subcutaneous DLBCL mouse model. Moreover, it shows high cytotoxic effect in CXCR4 + DLBCL cells, including induction of G2/M mitotic arrest, DNA damage, mitotic catastrophe and apoptosis. Furthermore, the nanoconjugate shows a potent reduction in lymphoma mouse dissemination without histopathological alterations in non-DLBCL infiltrated organs. Importantly, T22-AUR also exhibits lack of toxicity in human PBMCs. Conclusion T22-AUR exerts in vitro and in vivo anticancer effect on CXCR4 + DLBCL cells without off-target toxicity. Thus, T22-AUR promises to become an effective therapy for CXCR4 + DLBCL patients.

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Section: Discussionmentioning

confidence: 99%

“… 6 , 7 Here, we chose the CXCR4 receptor to target lymphoma cells, since around 30–50% of DLBCL biopsies overexpress this receptor (CXCR4 + ) 8 , 9 and its expression in lymphoma cells is much higher than in normal B cells. 10 Moreover, CXCR4 overexpression is a poor prognostic factor in DLBCL patients. 9 , 11 …”

Section: Introductionmentioning

confidence: 99%

Specific Cytotoxic Effect of an Auristatin Nanoconjugate Towards CXCR4+ Diffuse Large B-Cell Lymphoma Cells

Falgàs

Pallarès

Unzueta

et al. 2021

IJN

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The Importance of Tumor–Host Interactions in Adult B-Cell Leukemias and Lymphomas

Deaglio

Hartmann

2020

IJMS

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Distinct Chemokine Receptor Expression Profiles in De Novo DLBCL, Transformed Follicular Lymphoma, Richter’s Trans-Formed DLBCL and Germinal Center B-Cells

Uhl

Prochazka

Pansy

et al. 2022

IJMS

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Chemokine receptors and their ligands have been identified as playing an important role in the development of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and Richter syndrome (RS). Our aim was to investigate the different expression profiles in de novo DLBCL, transformed follicular lymphoma (tFL), and RS. Here, we profiled the mRNA expression levels of 18 chemokine receptors (CCR1–CCR9, CXCR1–CXCR7, CX3CR1 and XCR1) using RQ-PCR, as well as immunohistochemistry of seven chemokine receptors (CCR1, CCR4–CCR8 and CXCR2) in RS, de novo DLBCL, and tFL biopsy-derived tissues. Tonsil-derived germinal center B-cells (GC-B) served as non-neoplastic controls. The chemokine receptor expression profiles of de novo DLBCL and tFL substantially differed from those of GC-B, with at least 5-fold higher expression of 15 out of the 18 investigated chemokine receptors (CCR1–CCR9, CXCR1, CXCR2, CXCR6, CXCR7, CX3CR1 and XCR1) in these lymphoma subtypes. Interestingly, the de novo DLBCL and tFL exhibited at least 22-fold higher expression of CCR1, CCR5, CCR8, and CXCR6 compared with RS, whereas no significant difference in chemokine receptor expression profile was detected when comparing de novo DLBCL with tFL. Furthermore, in de novo DLBCL and tFLs, a high expression of CCR7 was associated with a poor overall survival in our study cohort, as well as in an independent patient cohort. Our data indicate that the chemokine receptor expression profile of RS differs substantially from that of de novo DLBCL and tFL. Thus, these multiple dysregulated chemokine receptors could represent novel clinical markers as diagnostic and prognostic tools. Moreover, this study highlights the relevance of chemokine signaling crosstalk in the tumor microenvironment of aggressive lymphomas.

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The CXCR4-CXCL12-Axis is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects in Vitro

Cited by 4 publications

References 47 publications

Specific Cytotoxic Effect of an Auristatin Nanoconjugate Towards CXCR4+ Diffuse Large B-Cell Lymphoma Cells

Specific Cytotoxic Effect of an Auristatin Nanoconjugate Towards CXCR4+ Diffuse Large B-Cell Lymphoma Cells

The Importance of Tumor–Host Interactions in Adult B-Cell Leukemias and Lymphomas

Distinct Chemokine Receptor Expression Profiles in De Novo DLBCL, Transformed Follicular Lymphoma, Richter’s Trans-Formed DLBCL and Germinal Center B-Cells

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