LFA-1-targeting Leukotoxin (LtxA; Leukothera®) causes lymphoma tumor regression in a humanized mouse model and requires caspase-8 and Fas to kill malignant lymphocytes

DiFranco, Kristina M.; Johnson-Farley, Nadine; Bertino, Joseph R.; Elson, David; Vega, Brian A.; Belinka, Benjamin A.; Kachlany, Scott C.

doi:10.1016/j.leukres.2015.03.010

Cited by 19 publications

(34 citation statements)

References 37 publications

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“…In contrast to myeloid cells, LtxA uses “slow mode” of lymphocyte killing. Killing of malignant lymphocytes requires Fas receptors and caspase 8 in both T and B lymphocytes [62]. In B lymphocytes (JY cells), LtxA caused loss of mitochondrial membrane potential, cytochrome c release, reactive oxygen species release, and activation of caspases 3,7,9 [26].…”

Section: Discussionmentioning

confidence: 99%

Aggregatibacter actinomycetemcomitansLtxA hijacks endocytic trafficking pathways in human lymphocytes

Lally

Boesze‐Battaglia

Dhingra

et al. 2019

Preprint

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Leukotoxin (LtxA) from oral pathogenAggregatibacter actinomycetemcomitansis a secreted membrane-damaging protein. LtxA is internalized by β2 integrin LFA-1 (CD11a/CD18) expressing leukocytes and ultimately causes cell death; however toxin localization in the host cell is poorly understood and these studies fill this void. We investigated LtxA trafficking using multi-fluor confocal imaging, flow cytometry and Rab5 knockdown in human T lymphocyte Jurkat cells. Planar lipid bilayers were used to characterize LtxA pore-forming activity at different pH. Our results demonstrate that LtxA/LFA-1 complex gains an access to the cytosol of Jurkat cells without evidence of plasma membrane damage utilizing dynamin-dependent and clathrin-independent mechanism. Upon internalization LtxA follows the LFA-1 endocytic trafficking pathways as identified by co-localization experiments with endosomal and lysosomal markers (Rab5, Rab11A, Rab7, and Lamp2) and CD11a. Knockdown of Rab5a resulted in loss of susceptibility of Jurkat cells to LtxA cytotoxicity suggesting that late events of LtxA endocytic trafficking are required for toxicity. The toxin trafficking via the degradation endocytic pathway may culminate in delivery of the protein to lysosomes or its accumulation in Rab11A-dependent recycling endosomes. The ability of LtxA to form pores at acidic pH may result in permeabilization of the endosomal and lysosomal membranes.

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Section: Discussionmentioning

confidence: 99%

Aggregatibacter actinomycetemcomitansLtxA hijacks endocytic trafficking pathways in human lymphocytes

Lally

Boesze‐Battaglia

Dhingra

et al. 2019

Preprint

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show abstract

“…DiFranco et al recently demonstrated that LtxA kills lymphoma cells in a caspase‐8‐dependent manner. The authors then screened a number of receptors and proteins that can activate caspase‐8, and identified the death receptor, Fas, as an essential component in the LtxA‐mediated killing of these cells (DiFranco et al, 2015). The researchers also observed decreased antibody binding when cells were pretreated with the toxin, suggesting that LtxA binds directly with the Fas receptor.…”

Section: Host Cell Interactionsmentioning

confidence: 99%

“…The interaction of LtxA with LFA‐1 and cholesterol appears to initiate an intracellular cascade of events that ultimately leads to apoptosis (Figure 3). While the entire mechanism is not yet known, it is important to note that evidence points to differing pathways in monocytes versus lymphocytes; however, the requirement of LFA‐1 is consistent between both cell types (DiFranco et al, 2012, 2015).…”

Section: Host Cell Interactionsmentioning

confidence: 99%

Aggregatibacter actinomycetemcomitans leukotoxin: From mechanism to targeted anti‐toxin therapeutics

Krueger

Brown

2020

Molecular Oral Microbiology

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Aggregatibacter actinomycetemcomitans is a Gram-negative bacterium associated with localized aggressive periodontitis, as well as other systemic diseases. This organism produces a number of virulence factors, all of which provide some advantage to the bacterium. Several studies have demonstrated that clinical isolates from diseased patients, particularly those of African descent, frequently belong to specific clones of A. actinomycetemcomitans that produce significantly higher amounts of a protein exotoxin belonging to the repeats-in-toxin (RTX) family, leukotoxin (LtxA), whereas isolates from healthy patients harbor minimally leukotoxic strains. This finding suggests that LtxA might play a key role in A. actinomycetemcomitans pathogenicity. Because of this correlation, much work over the past 30 years has been focused on understanding the mechanisms by which LtxA interacts with and kills host cells.In this article, we review those findings, highlight the remaining open questions, and demonstrate how knowledge of these mechanisms, particularly the toxin's interactions with lymphocyte function-associated antigen-1 (LFA-1) and cholesterol, enables the design of targeted anti-LtxA strategies to prevent/treat disease. K E Y W O R D SAggregatibacter actinomycetemcomitans, leukotoxin, LFA-1, repeats-in-toxin

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“…It binds to activated LFA-1 and induces apoptosis by several mechanisms [62]. Leukotoxin shows a tendency to kill leukemic cells in a LFA-1-dependent manner [63] [64]. Whereas normal hematopoietic cells might be partially sensitive, leukotoxin shows preferential activity against active LFA-1 and spares most blood cells.…”

Section: The Effect Of Leukotoxinmentioning

confidence: 99%

“…Whereas normal hematopoietic cells might be partially sensitive, leukotoxin shows preferential activity against active LFA-1 and spares most blood cells. The death of tumor lymphocytes occurred by a Fasdependent mechanism [64]. Besides the advantage of counting with a potential therapeutic tool, working out the mechanism behind leukotoxin's action on LFA-1 leading to cell death, will provide new knowledge linking adhesion to cell fate decisions.…”

Section: The Effect Of Leukotoxinmentioning

confidence: 99%

Role of LFA-1 and ICAM-1 in Cancer

Reina

Espel

2017

Preprint

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The lymphocyte function-associated antigen-1 (LFA-1) (also CD11a/CD18 and αLβ2), is just one of many integrins in the human body, but its significance derives from its exclusive presence in leukocytes. In this review, we summarize the studies relating LFA-1 and its major ligand ICAM-1 (CD54) with cancer, through the function of lymphocytes and myeloid cells on tumor cells. We consider how LFA-1 mediates the interaction of leukocytes with tumors and the role of ICAM-1 in tumor dynamics, which can be independent of its interaction with LFA-1. A more detailed examination of LFA's role within B-cell chronic lymphocytic leukemia is made. Finally, we discuss the role of LFA-1-harboring exosomes in tumor growth and metastasis.Keywords: cancer metastasis; chronic lymphocytic leukemia; exosomes; tumor microenvironment LFA-1 is widely expressed in hematopoietic cells, mediating intercellular interactions within the immune system and between leukocytes and non-blood cells. Several intercellular adhesion molecules (ICAM), including ICAM-1 (CD54) are common ligands for LFA-1 [1] [2]. The strength of LFA-1 adhesion varies by adjusting the affinity (conformation), the level of LFA-1 clustering and the force applied by the ligand [3] [4] [5]. LFA-1 can adopt different conformations, from a folded low-affinity inactive one to an open active conformation. The stimulation of cells by receptors like the T-cell receptor or chemokine receptors changes the adhesive properties of LFA-1 in a process called "inside-out" signaling that may open the conformation of LFA-1 and expose its ligand-binding site [6]. In addition, it should be noted that the characteristics of the external ligand binding to LFA-1 initiates a signaling cascade in LFA-1 (named "outside-in" signaling), giving rise to various cellular changes [7]. As with other integrins, LFA-1 is not a mere adhesive contact between cells, but it also mediates signals that modulate the growth, differentiation and survival of the cell. LFA-1 participates in the cytotoxic immune response against tumorsThe T cell cytotoxic response against cancer cells starts when the T cell receptor recognizes a specific tumor antigen on the surface of the cancer cell; this is normally followed by delivery of toxic granules that kill the target cell. In the cytolytic response against virus-infected cells, the adhesion between the cytotoxic lymphocyte and the target cell is not strictly dependent on LFA-1, this however is necessary in the cytolytic response to immunogenic tumors [8] [9]. LFA-1 is an essential initiator of the immunological synapse that forms between the cytotoxic T or NK cell and the cancer cell, and mediates the firm adhesion to the target cell and the polarization of cytotoxic granules towards the target [7] [10] [11]. There is a positive correlation between the maturation state of NK cells, their cytotoxic potential and the activation level of LFA-1 [12].Tumor infiltrating lymphocytes need LFA-1 to adhere to target cells Cancer cells can escape from the immune response by chan...

show abstract

LFA-1-targeting Leukotoxin (LtxA; Leukothera®) causes lymphoma tumor regression in a humanized mouse model and requires caspase-8 and Fas to kill malignant lymphocytes

Cited by 19 publications

References 37 publications

Aggregatibacter actinomycetemcomitansLtxA hijacks endocytic trafficking pathways in human lymphocytes

Aggregatibacter actinomycetemcomitansLtxA hijacks endocytic trafficking pathways in human lymphocytes

Aggregatibacter actinomycetemcomitans leukotoxin: From mechanism to targeted anti‐toxin therapeutics

Role of LFA-1 and ICAM-1 in Cancer

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