Expression of sialyl-Tn sugar antigen in bladder cancer cells affects response to <i>Bacillus Calmette Guérin</i> (BCG) and to oxidative damage

Severino, Paulo F.; Silva, Mariana; Carrascal, Mylène A.; Malagolini, Nadia; Chiricolo, Mariella; Venturi, Giulia; Astolfi, Annalisa; Catera, Mariangela; Videira, Paula A.; Dall’Olio, Fabio

doi:10.18632/oncotarget.17138

Cited by 19 publications

(13 citation statements)

References 38 publications

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“…Worth mentioning, IL-6, which is mainly held responsible for cytokine release syndrome, was detected in supernatants of samples containing target cells regardless of the presence or absence of the αSTn-IgG4 TM. This suggests that IL-6 is released by MDA-MB-231 and MCR cancer cells and not by activated UniCAR T-cells, which is in line with our previous publication and other studies [12,35,36]. As stated before, proinflammatory cytokines are specifically released following TMdependent cross-linkage of tumor and UniCAR T-cells.…”

Section: Discussionsupporting

confidence: 91%

Extended half-life target module for sustainable UniCAR T-cell treatment of STn-expressing cancers

Loureiro

Feldmann

Bergmann

et al. 2020

J Exp Clin Cancer Res

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Background: Adapter chimeric antigen receptor (CAR) approaches have emerged has promising strategies to increase clinical safety of CAR T-cell therapy. In the UniCAR system, the safety switch is controlled via a target module (TM) which is characterized by a small-size and short half-life. The rapid clearance of these TMs from the blood allows a quick steering and self-limiting safety switch of UniCAR T-cells by TM dosing. This is mainly important during onset of therapy when tumor burden and the risk for severe side effects are high. For long-term UniCAR therapy, the continuous infusion of TMs may not be an optimal setting for the patients. Thus, in later stages of treatment, single infusions of TMs with an increased half-life might play an important role in long-term surveillance and eradication of residual tumor cells. Given this, we aimed to develop and characterize a novel TM with extended half-life targeting the tumor-associated carbohydrate sialyl-Tn (STn). Methods: The extended half-life TM is composed of the STn-specific single-chain variable fragment (scFv) and the UniCAR epitope, fused to the hinge region and Fc domain of a human immunoglobulin 4 (IgG4) antibody. Specific binding and functionality of the αSTn-IgG4 TM as well as pharmacokinetic features were assessed using in vitro and in vivo assays and compared to the already established small-sized αSTn TM. Results: The novel αSTn-IgG4 TM efficiently activates and redirects UniCAR T-cells to STn-expressing tumors in a target-specific and TM-dependent manner, thereby promoting the secretion of proinflammatory cytokines and tumor cell lysis in vitro and in experimental mice. Moreover, PET-imaging results demonstrate the specific enrichment of the αSTn-IgG4 TM at the tumor site, while presenting a prolonged serum half-life compared to the short-lived αSTn TM. Conclusion: In a clinical setting, the combination of TMs with different formats and pharmacokinetics may represent a promising strategy for retargeting of UniCAR T-cells in a flexible, individualized and safe manner at particular stages of therapy. Furthermore, as these molecules can be used for in vivo imaging, they pose as attractive candidates for theranostic approaches.

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Section: Discussionsupporting

confidence: 91%

Extended half-life target module for sustainable UniCAR T-cell treatment of STn-expressing cancers

Loureiro

Feldmann

Bergmann

et al. 2020

J Exp Clin Cancer Res

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“…For this reason, we investigated the effect of B4GALNT2 on the transcriptome of transfected LS174T cell variants. The ability to modulate the transcriptome of cancer cells by a glycosyltransferase was previously documented [17,[24][25][26]. Nevertheless, the transcriptomic changes induced by B4GALNT2 in standard conditions of growth were surprisingly relevant.…”

Section: Discussionmentioning

confidence: 93%

High Expression of the Sda Synthase B4GALNT2 Associates with Good Prognosis and Attenuates Stemness in Colon Cancer

Pucci

Ferreira

Orlandani

et al. 2020

Cells

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Background: The carbohydrate antigen Sda and its biosynthetic enzyme B4GALNT2 are highly expressed in normal colonic mucosa but are down-regulated to a variable degree in colon cancer tissues. Here, we investigated the clinical and biological importance of B4GALNT2 in colon cancer. Methods: Correlations of B4GALNT2 mRNA with clinical data were obtained from The Cancer Genome Atlas (TCGA) database; the phenotypic and transcriptomic changes induced by B4GALNT2 were studied in LS174T cells transfected with B4GALNT2 cDNA. Results: TCGA data indicate that patients with high B4GALNT2 expression in cancer tissues display longer survival than non-expressers. In LS174T cells, expression of B4GALNT2 did not affect the ability to heal a scratch wound or to form colonies in standard growth conditions but markedly reduced the growth in soft agar, the tridimensional (3D) growth as spheroids, and the number of cancer stem cells, indicating a specific effect of B4GALNT2 on the growth in poor adherence and stemness. On the transcriptome, B4GALNT2 induced the down-regulation of the stemness-associated gene SOX2 and modulated gene expression towards an attenuation of the cancer phenotype. Conclusions: The level of B4GALNT2 can be proposed as a marker to identify higher- and lower-risk colorectal cancer patients.

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“…Sialyl-Tn-and sialyl-Tn/S6T-expressing bladder tumors were treated with bacillus Calmette-Guerin (BCG) [88,89]. Lower recurrence rates of sialyl-Tn-positive tumor cells were observed post-BCG treatment.…”

Section: Mechanistic Insights Of St6galnac-i In Different Bladder Tumormentioning

confidence: 99%

A Systematic Review on the Implications of O-linked Glycan Branching and Truncating Enzymes on Cancer Progression and Metastasis

Gupta

Leon

Rauth

et al. 2020

Cells

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Glycosylation is the most commonly occurring post-translational modifications, and is believed to modify over 50% of all proteins. The process of glycan modification is directed by different glycosyltransferases, depending on the cell in which it is expressed. These small carbohydrate molecules consist of multiple glycan families that facilitate cell–cell interactions, protein interactions, and downstream signaling. An alteration of several types of O-glycan core structures have been implicated in multiple cancers, largely due to differential glycosyltransferase expression or activity. Consequently, aberrant O-linked glycosylation has been extensively demonstrated to affect biological function and protein integrity that directly result in cancer growth and progression of several diseases. Herein, we provide a comprehensive review of several initiating enzymes involved in the synthesis of O-linked glycosylation that significantly contribute to a number of different cancers.

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Expression of sialyl-Tn sugar antigen in bladder cancer cells affects response to Bacillus Calmette Guérin (BCG) and to oxidative damage

Cited by 19 publications

References 38 publications

Extended half-life target module for sustainable UniCAR T-cell treatment of STn-expressing cancers

Extended half-life target module for sustainable UniCAR T-cell treatment of STn-expressing cancers

High Expression of the Sda Synthase B4GALNT2 Associates with Good Prognosis and Attenuates Stemness in Colon Cancer

A Systematic Review on the Implications of O-linked Glycan Branching and Truncating Enzymes on Cancer Progression and Metastasis

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