Transient regulatory T-cell targeting triggers immune control of multiple myeloma and prevents disease progression

Dahlhoff, Julia; Manz, Hannah; Steinfatt, Tim; Delgado-Tascon, Julia; Seebacher, Elena; Schneider, Theresa; Wilnit, Amy; Mokhtari, Zeinab; Tabares, Paula; Böckle, David; Rasche, Leo; Kortüm, K. Martin; Lutz, Manfred B.; Einsele, Hermann; Brandl, Andreas; Beilhack, Andreas

doi:10.1038/s41375-021-01422-y

Cited by 28 publications

(16 citation statements)

References 58 publications

(83 reference statements)

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“…This may explain our results, in which activation of CD8 + T cells, as well as the high abundance of memory T cells, significantly prolongs the OS time of CC patients. Surprisingly, the results showed that high Treg infiltration was significantly associated with good prognosis of patients, which was quite opposite to the phenomenon widely reported thus far ( Banerjee et al, 2021 ; Dahlhoff et al, 2021 ; Peng et al, 2021 ). In previous reports, little literature has mentioned that Treg can participate in the immune process as a protective factor.…”

Section: Discussioncontrasting

confidence: 98%

Fanconi Anemia Pathway Genes Advance Cervical Cancer via Immune Regulation and Cell Adhesion

Wang

Ding

Cui

et al. 2021

Front. Cell Dev. Biol.

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Fanconi anemia (FA) pathway is a typical and multienzyme-regulated DNA damage repairer that influences the occurrence and development of disease including cancers. Few comprehensive analyses were reported about the role of FA-related genes (FARGs) and their prognostic values in cancers. In this study, a comprehensive pan-cancer analysis on 79 FARGs was performed. According to the correlation analyses between HPV integration sites and FARGs, we found that FARGs played specific and critical roles in HPV-related cancers, especially in cervical cancer (CC). Based on this, a FARGs-associated prognostic risk score (FPS) model was constructed, and subsequently a nomogram model containing the FPS was developed with a good accuracy for CC overall survival (OS) and recurrence-free survival (RFS) outcome prediction. We also used the similar expression pattern of FARGs by consensus clustering analysis to separate the patients into three subgroups that exhibited significant differential OS but not RFS. Moreover, differential expressed genes (DEGs) between the two risk groups or three clusters were identified and immune pathways as well as cell adhesion processes were determined by functional enrichment analysis. Results indicated that FARGs might promote occurrence and development of CC by regulating the immune cells’ infiltration and cell adhesion. In addition, through the machine learning models containing decision tree, random forest, naïve bayes, and support vector machine models, screening of important variables on CC prognosis, we finally determined that ZBTB32 and CENPS were the main elements affecting CC OS, while PALB2 and BRCA2 were for RFS. Kaplan-Meier analysis revealed that bivariate prediction of CC outcome was reliable. Our study systematically analyzed the prognostic prediction values of FARGs and demonstrated their potential mechanism in CC aggressiveness. Results provided perspective in FA pathway-associated modification and theoretical basis for CC clinical treatments.

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Section: Discussioncontrasting

confidence: 98%

Fanconi Anemia Pathway Genes Advance Cervical Cancer via Immune Regulation and Cell Adhesion

Wang

Ding

Cui

et al. 2021

Front. Cell Dev. Biol.

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“…C57BL/6 (“B6”) and FVB/N mice were obtained from Janvier Labs (Le Genest Saint Isle, France). Albino C57BL/6J-Tyr c-2J /J (“B6a”), albino C57BL/6J-Tyr c-2J /Foxp3.Luci.DTR-4 (“FoxP3-Luci-DTR”) ( 21 , 22 ), albino C57BL/6-Tyr c-2J /129S2-Tnfrsf1b tm1Mwm /J (“TNFR2-KO”), FVB/N.L2G85 (“FVB-Luci + ”) and C57BL/6J.L2G85-CD90.1 (“B6-Luci + ”) ( 23 , 24 ), were bred at the Center for Experimental Molecular Medicine (ZEMM) in Würzburg, Germany. All mice were housed in the specific pathogen-free facility of the ZEMM, and experiments were carried out according to the German regulations and reviewed and approved by the governmental authorities (Regierung von Unterfranken, 55.2.2-2532-2-537-61 and 55.2.2-2532-2-410-75).…”

Section: Methodsmentioning

confidence: 99%

“…For in vivo Treg expansion experiments and GvHD studies luciferase-transgenic FoxP3-Luci-DTR mice that express eGFP and luciferase under the FoxP3 promoter ( 21 , 22 ) or B6 WT mice, respectively, were injected intraperitoneally (i.p.) with 140 µg of NewSTAR2 or the same volume of PBS.…”

Section: Methodsmentioning

confidence: 99%

A TNFR2-Specific TNF Fusion Protein With Improved In Vivo Activity

et al. 2022

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Tumor necrosis factor (TNF) receptor-2 (TNFR2) has attracted considerable interest as a target for immunotherapy. Indeed, using oligomeric fusion proteins of single chain-encoded TNFR2-specific TNF mutants (scTNF80), expansion of regulatory T cells and therapeutic activity could be demonstrated in various autoinflammatory diseases, including graft-versus-host disease (GvHD), experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). With the aim to improve the in vivo availability of TNFR2-specific TNF fusion proteins, we used here the neonatal Fc receptor (FcRn)-interacting IgG1 molecule as an oligomerizing building block and generated a new TNFR2 agonist with improved serum retention and superior in vivo activity.MethodsSingle-chain encoded murine TNF80 trimers (sc(mu)TNF80) were fused to the C-terminus of an in mice irrelevant IgG1 molecule carrying the N297A mutation which avoids/minimizes interaction with Fcγ-receptors (FcγRs). The fusion protein obtained (irrIgG1(N297A)-sc(mu)TNF80), termed NewSTAR2 (New selective TNF-based agonist of TNF receptor 2), was analyzed with respect to activity, productivity, serum retention and in vitro and in vivo activity. STAR2 (TNC-sc(mu)TNF80 or selective TNF-based agonist of TNF receptor 2), a well-established highly active nonameric TNFR2-specific variant, served as benchmark. NewSTAR2 was assessed in various in vitro and in vivo systems.ResultsSTAR2 (TNC-sc(mu)TNF80) and NewSTAR2 (irrIgG1(N297A)-sc(mu)TNF80) revealed comparable in vitro activity. The novel domain architecture of NewSTAR2 significantly improved serum retention compared to STAR2, which correlated with efficient binding to FcRn. A single injection of NewSTAR2 enhanced regulatory T cell (Treg) suppressive activity and increased Treg numbers by > 300% in vivo 5 days after treatment. Treg numbers remained as high as 200% for about 10 days. Furthermore, a single in vivo treatment with NewSTAR2 upregulated the adenosine-regulating ectoenzyme CD39 and other activation markers on Tregs. TNFR2-stimulated Tregs proved to be more suppressive than unstimulated Tregs, reducing conventional T cell (Tcon) proliferation and expression of activation markers in vitro. Finally, singular preemptive NewSTAR2 administration five days before allogeneic hematopoietic cell transplantation (allo-HCT) protected mice from acute GvHD.ConclusionsNewSTAR2 represents a next generation ligand-based TNFR2 agonist, which is efficiently produced, exhibits improved pharmacokinetic properties and high serum retention with superior in vivo activity exerting powerful protective effects against acute GvHD.

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“…On the other side, some reports demonstrate that higher numbers of T-regs in tumors associate with better prognosis in patients [ 172 ], suggesting that the exact prognostic significance of T-regs cells is still unclear, and further studies need to be done. For instance, preclinical studies based on a transient T-reg depletion have demonstrated immune control of MM and prevented disease progression [ 117 ].…”

Section: Impact Of Interactions Between Immune Cells and MM Cells In ...mentioning

confidence: 99%

A Journey through the Inter-Cellular Interactions in the Bone Marrow in Multiple Myeloma: Implications for the Next Generation of Treatments

Hervás-Salcedo

Martín-Antonio

2022

Cancers

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Tumors are composed of a plethora of extracellular matrix, tumor and non-tumor cells that form a tumor microenvironment (TME) that nurtures the tumor cells and creates a favorable environment where tumor cells grow and proliferate. In multiple myeloma (MM), the TME is the bone marrow (BM). Non-tumor cells can belong either to the non-hematological compartment that secretes soluble mediators to create a favorable environment for MM cells to grow, or to the immune cell compartment that perform an anti-MM activity in healthy conditions. Indeed, marrow-infiltrating lymphocytes (MILs) are associated with a good prognosis in MM patients and have served as the basis for developing different immunotherapy strategies. However, MM cells and other cells in the BM can polarize their phenotype and activity, creating an immunosuppressive environment where immune cells do not perform their cytotoxic activity properly, promoting tumor progression. Understanding cell–cell interactions in the BM and their impact on MM proliferation and the performance of tumor surveillance will help in designing efficient anti-MM therapies. Here, we take a journey through the BM, describing the interactions of MM cells with cells of the non-hematological and hematological compartment to highlight their impact on MM progression and the development of novel MM treatments.

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Transient regulatory T-cell targeting triggers immune control of multiple myeloma and prevents disease progression

Cited by 28 publications

References 58 publications

Fanconi Anemia Pathway Genes Advance Cervical Cancer via Immune Regulation and Cell Adhesion

Fanconi Anemia Pathway Genes Advance Cervical Cancer via Immune Regulation and Cell Adhesion

A TNFR2-Specific TNF Fusion Protein With Improved In Vivo Activity

A Journey through the Inter-Cellular Interactions in the Bone Marrow in Multiple Myeloma: Implications for the Next Generation of Treatments

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