Actin stabilizer TAGLN2 potentiates adoptive T cell therapy by boosting the inside-out costimulation via lymphocyte function-associated antigen-1

Jeon, Bu‐Nam; Kim, Hye‐Ran; Chung, Yun Shin; Na, Bo-Ra; Park, Hyunkyung; Hong, Che Ry; Fatima, Yasmin; Oh, Hyeonju; Kim, Chang‐Hyun; Jun, Chang‐Duk

doi:10.1080/2162402x.2018.1500674

Cited by 14 publications

(23 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This in turn attenuated overall CTL killing activity. Forced over-expression of the dual actin and LFA-1 binding protein TGLN2 in CTL yielded stronger killing activity in case of ICAM-1-expressing but not ICAM-deficient antigen-presenting tumor cells [162]. This observation suggested TGLN2-dependent inside-out activation of LFA-1.…”

Section: Leukocyte/target Cell Interactionmentioning

confidence: 87%

β2 Integrins—Multi-Functional Leukocyte Receptors in Health and Disease

Bednarczyk

Stege

Grabbe

et al. 2020

IJMS

View full text Add to dashboard Cite

β2 integrins are heterodimeric surface receptors composed of a variable α (CD11a-CD11d) and a constant β (CD18) subunit and are specifically expressed by leukocytes. The α subunit defines the individual functional properties of the corresponding β2 integrin, but all β2 integrins show functional overlap. They mediate adhesion to other cells and to components of the extracellular matrix (ECM), orchestrate uptake of extracellular material like complement-opsonized pathogens, control cytoskeletal organization, and modulate cell signaling. This review aims to delineate the tremendous role of β2 integrins for immune functions as exemplified by the phenotype of LAD-I (leukocyte adhesion deficiency 1) patients that suffer from strong recurrent infections. These immune defects have been largely attributed to impaired migratory and phagocytic properties of polymorphonuclear granulocytes. The molecular base for this inherited disease is a functional impairment of β2 integrins due to mutations within the CD18 gene. LAD-I patients are also predisposed for autoimmune diseases. In agreement, polymorphisms within the CD11b gene have been associated with autoimmunity. Consequently, β2 integrins have received growing interest as targets in the treatment of autoimmune diseases. Moreover, β2 integrin activity on leukocytes has been implicated in tumor development.

show abstract

Section: Leukocyte/target Cell Interactionmentioning

confidence: 87%

β2 Integrins—Multi-Functional Leukocyte Receptors in Health and Disease

Bednarczyk

Stege

Grabbe

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…*P < 0.05; **P < 0. [17]. Indeed, LFA-1 is an essential initiator for the formation of the IS between cytotoxic T cells and cancer cells, and it mediates the polarization of cytotoxic granules toward target cells via tight adhesion to the target cells [35].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, its upregulation is correlated with the clinical stage, tumor size, and invasion in a wide spectrum of cancers [ 15 ]. We previously found that transgelin-2 is also expressed in lymphocytes and functions to stabilize the immunological synapse, thereby enhancing T cell activation [ 16 , 17 ]. It is also involved in filopodium initiation and/or elongation presumably by interfering with the interaction between the Arp2/3 complex and actin [ 18 ], which may drive the enhanced phagocytic behavior of macrophages toward invading bacteria [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Cell-permeable transgelin-2 as a potent therapeutic for dendritic cell-based cancer immunotherapy

Kim

Park

et al. 2021

J Hematol Oncol

Self Cite

View full text Add to dashboard Cite

Background Transgelin-2 is a 22 kDa actin-binding protein that has been proposed to act as an oncogenic factor, capable of contributing to tumorigenesis in a wide range of human malignancies. However, little is known whether this tiny protein also plays an important role in immunity, thereby keeping body from the cancer development and metastasis. Here, we investigated the functions of transgelin-2 in dendritic cell (DC) immunity. Further, we investigated whether the non-viral transduction of cell-permeable transgelin-2 peptide potentially enhance DC-based cancer immunotherapy. Methods To understand the functions of transgelin-2 in DCs, we utilized bone marrow-derived DCs (BMDCs) purified from transgelin-2 knockout (Tagln2−/−) mice. To observe the dynamic cellular mechanism of transgelin-2, we utilized confocal microscopy and flow cytometry. To monitor DC migration and cognate T–DC interaction in vivo, we used intravital two-photon microscopy. For the solid and metastasis tumor models, OVA+ B16F10 melanoma were inoculated into the C57BL/6 mice via intravenously (i.v.) and subcutaneously (s.c.), respectively. OTI TCR T cells were used for the adoptive transfer experiments. Cell-permeable, de-ubiquitinated recombinant transgelin-2 was purified from Escherichia coli and applied for DC-based adoptive immunotherapy. Results We found that transgelin-2 is remarkably expressed in BMDCs during maturation and lipopolysaccharide activation, suggesting that this protein plays a role in DC-based immunity. Although Tagln2−/− BMDCs exhibited no changes in maturation, they showed significant defects in their abilities to home to draining lymph nodes (LNs) and prime T cells to produce antigen-specific T cell clones, and these changes were associated with a failure to suppress tumor growth and metastasis of OVA+ B16F10 melanoma cells in mice. Tagln2−/− BMDCs had defects in filopodia-like membrane protrusion and podosome formation due to the attenuation of the signals that modulate actin remodeling in vitro and formed short, unstable contacts with cognate CD4+ T cells in vivo. Strikingly, non-viral transduction of cell-permeable, de-ubiquitinated recombinant transgelin-2 potentiated DC functions to suppress tumor growth and metastasis. Conclusion This work demonstrates that transgelin-2 is an essential protein for both cancer and immunity. Therefore, transgelin-2 can act as a double-edged sword depending on how we apply this protein to cancer therapy. Engineering and clinical application of this protein may unveil a new era in DC-based cancer immunotherapy. Our findings indicate that cell-permeable transgelin-2 have a potential clinical value as a cancer immunotherapy based on DCs.

show abstract

“…TAGLN2, an actinbinding protein, can regulate cell morphology, movement and transformation by binding to actin. TAGLN2 is abnormally expressed in a variety of cancers (18), and its deregulation is considered to be correlated with tumorigenesis and tumor development. In gliomas, TAGLN2 is a potential oncogenic factor, which is regulated by TGFβ2 to promote glioma invasion and growth (19).…”

Section: Discussionmentioning

confidence: 99%

Systematic analysis of 4-gene prognostic signature in patients with diffuse gliomas based on gene expression profiles

Huang

Xiong

Li³

2020

Preprint

View full text Add to dashboard Cite

Background: Diffuse gliomas are a group of diseases that contain different degrees of malignancy and complex heterogeneity. Previous studies proposed biomarkers for certain grades of gliomas, but few of them have conducted a systematic analysis of different grades to search for molecular markers.Methods: WGCNA was used to find significant genes associated with malignant progression of diffuse glioma in TCGA glioma sequencing expression data and the GEO expression profile-merge meta dataset. Lasso regression was used for potential model building and the best model was selected by CPE, IDI and C_index. Risk score model was used to evaluate the gene signature prognostic power.Multi-omics data, including CNV, methylation, clinical traits and mutation, were used for model evaluation.Results: We find out 67 genes significantly associated with malignant progression of diffuse glioma by WGCNA. Next, we establish a new 4 gene molecular marker (KDELR2, EMP3, TIMP1, and TAGLN2).Multivariate cox analysis identified the risk score of the 4 genes as an independent predictor of prognosis in patients with diffuse gliomas, and its predictive power was independent of the histopathological grades of glioma. Further, we had confirmed in five independent test datasets and the risk score remained good predictive power. The combination of the prognosis model with specific molecular characteristics possessed better predictive power than risk score solely and we divided the low-risk group into three subtypes: LowRisk_IDH1wt, LowRisk_IDH1mut/ATRXmut, and LowRisk_IDH1mut/ATRXwt by combining IDH1 mutation with ATRX mutation, which possessed obvious survival difference. In further analysis, we found that the 4 gene prognosis model possessed multiomics features.Conclusion: we established a malignant-related 4-gene molecular marker by glioma expression profile data from multiple microarrays and sequencing data. The four markers had good predictive power on the overall survival of glioma patients and were associated with gliomas' clinical and genetic backgrounds, including clinical features, gene mutation, methylation, CNV, signal pathways.

show abstract

Actin stabilizer TAGLN2 potentiates adoptive T cell therapy by boosting the inside-out costimulation via lymphocyte function-associated antigen-1

Cited by 14 publications

References 43 publications

β2 Integrins—Multi-Functional Leukocyte Receptors in Health and Disease

β2 Integrins—Multi-Functional Leukocyte Receptors in Health and Disease

Cell-permeable transgelin-2 as a potent therapeutic for dendritic cell-based cancer immunotherapy

Systematic analysis of 4-gene prognostic signature in patients with diffuse gliomas based on gene expression profiles

Contact Info

Product

Resources

About