High CD123 levels enhance proliferation in response to IL-3, but reduce chemotaxis by downregulating CXCR4 expression

Wittwer, Nicole L; Brumatti, Gabriela; Marchant, Ceilidh; Sandow, Jarrod J.; Pudney, Melanie K.; Dottore, Mara; D’Andrea, Richard J.; Lopez, Angel F.; Ekert, Paul G.; Ramshaw, Hayley S.

doi:10.1182/bloodadvances.2016002931

Cited by 27 publications

(27 citation statements)

References 63 publications

(70 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…50 51 Fourth, CD123 expression enhance AML cell proliferation and induces downregulation of CXCR4, favoring the egress of BM AML-LSCs into the circulation. 52 Based on this background, we prompted to characterize and compare in vitro and in vivo the efficacy and safety profile of the second-generation 41BB-based and CD28-based CD123CARs derived from the clinically tested CSL362 humanized MoAb. 14 53 Regardless of the costimulation motif, CD123 CARTs were very efficient in vitro and in vivo in eliminating both AML cell lines and primary cells, even at relatively low E:T ratios.…”

Section: Open Accessmentioning

confidence: 99%

41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo

Baroni

Martinez

Agüera

et al. 2020

J Immunother Cancer

View full text Add to dashboard Cite

BackgroundAcute myeloid leukemia (AML) is a hematopoietic malignancy which is biologically, phenotypically and genetically very heterogeneous. Outcome of patients with AML remains dismal, highlighting the need for improved, less toxic therapies. Chimeric antigen receptor T-cell (CART) immunotherapies for patients with refractory or relapse (R/R) AML are challenging because of the absence of a universal pan-AML target antigen and the shared expression of target antigens with normal hematopoietic stem/progenitor cells (HSPCs), which may lead to life-threating on-target/off-tumor cytotoxicity. CD33-redirected and CD123-redirected CARTs for AML are in advanced preclinical and clinical development, and they exhibit robust antileukemic activity. However, preclinical and clinical controversy exists on whether such CARTs are myeloablative.MethodsWe set out to comparatively characterize in vitro and in vivo the efficacy and safety of 41BB-based and CD28-based CARCD123. We analyzed 97 diagnostic and relapse AML primary samples to investigate whether CD123 is a suitable immunotherapeutic target, and we used several xenograft models and in vitro assays to assess the myeloablative potential of our second-generation CD123 CARTs.ResultsHere, we show that CD123 represents a bona fide target for AML and show that both 41BB-based and CD28-based CD123 CARTs are very efficient in eliminating both AML cell lines and primary cells in vitro and in vivo. However, both 41BB-based and CD28-based CD123 CARTs ablate normal human hematopoiesis and prevent the establishment of de novo hematopoietic reconstitution by targeting both immature and myeloid HSPCs.ConclusionsThis study calls for caution when clinically implementing CD123 CARTs, encouraging its preferential use as a bridge to allo-HSCT in patients with R/R AML.

show abstract

Section: Open Accessmentioning

confidence: 99%

41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo

Baroni

Martinez

Agüera

et al. 2020

J Immunother Cancer

View full text Add to dashboard Cite

show abstract

“…Here, we provide an evidence that CpG ODN can increase the percentage of CD123+ on T and B lymphocyte subsets, as well as monocyte population when compared to unstimulated cells. It is possible that part of the effect we observed here was related to enhanced IL3R signaling that has been shown to promote proliferation and cell viability (Macardle et al, 1996;Teleshova et al, 2006;Wittwer et al, 2017). The disparity between the CD123 co-expression levels observed in CpG ODN-stimulated peripheral blood (s.c injection) and in CpG ODN-stimulated SQM PBMCs may be caused by varying differentiation stages of specific analyzed cell subsets at the time of stimulation with CpG ODN.…”

Section: Discussionmentioning

confidence: 85%

Class C CpG Oligodeoxynucleotide Immunomodulatory Response in Aged Squirrel Monkey (Saimiri Boliviensis Boliviensis)

Nehete

Williams

Chitta

et al. 2020

Front. Aging Neurosci.

View full text Add to dashboard Cite

One means of stimulating the mammalian innate immune system is via Toll-like receptor 9 (TLR9) being exposed to unmethylated cytosine-phosphate-guanine (CpG) DNA, also known as pathogen-associated molecular patterns (PAMPs) of microbial origin. Synthetic CpG oligodeoxynucleotides (ODNs) with defined CpG motifs possess broad immunostimulatory properties that make CpG ODNs suitable as therapeutic interventions in a variety of human disease conditions, including Alzheimer's disease (AD). Rodent models are often used to preclinically test the effectiveness of CpG ODN therapeutic agents for AD and other disorders. However, the translatability of findings in such models is limited due to the significant difference of the expression of TLR9 between primates and rodents. The squirrel monkey (SQM), a New World non-human primate (NHP), is known to be phylogenetically proximate to humans, and develops extensive age-dependent cerebral amyloid angiopathy (CAA), a key pathological feature of AD. Hence, this model is currently being used to test AD therapeutics. In the present study, we conducted the first examination of Class C CpG ODN's immunomodulatory role in elderly SQMs. We documented the effectiveness of CpG ODN to trigger an immune response in an aged cohort whose immune system is senescent. The specific immune response patterns detected here closely resembled CpG ODN-induced immunostimulatory patterns observed in prior human studies. Overall, our findings provide critical data regarding the immunomodulatory potential of CpG ODN in this NHP model, allowing for future translational studies of innate immunity stimulation via TLR9 agonists for diverse indications, including AD therapeutics.

show abstract

“…6b ), we wondered if this contributed to the differences in IL-3 function. Using a TF-1 cell line engineered to overexpress IL3Rα 26 (Supplementary Fig. 6b ), we observed that wild-type IL-3 and IL-3 K116W are functionally indistinguishable (ED 50 = 0.005 ng ml −1 each, Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The human erythroleukaemia cell line, TF-1 65 (ATCC CRL-2003) was transduced with lentiviral vectors encoding GFP alone or IL3Rα and GFP 26 to produce the TF-1EV and TF-1Hi lines, respectively. Cell-surface expression levels of IL3Rα and βc was measured by flow cytometry.…”

Section: Methodsmentioning

confidence: 99%

A dual role for the N-terminal domain of the IL-3 receptor in cell signalling

et al. 2018

Self Cite

View full text Add to dashboard Cite

The interleukin-3 (IL-3) receptor is a cell-surface heterodimer that links the haemopoietic, vascular and immune systems and is overexpressed in acute and chronic myeloid leukaemia progenitor cells. It belongs to the type I cytokine receptor family in which the α-subunits consist of two fibronectin III-like domains that bind cytokine, and a third, evolutionarily unrelated and topologically conserved, N-terminal domain (NTD) with unknown function. Here we show by crystallography that, while the NTD of IL3Rα is highly mobile in the presence of IL-3, it becomes surprisingly rigid in the presence of IL-3 K116W. Mutagenesis, biochemical and functional studies show that the NTD of IL3Rα regulates IL-3 binding and signalling and reveal an unexpected role in preventing spontaneous receptor dimerisation. Our work identifies a dual role for the NTD in this cytokine receptor family, protecting against inappropriate signalling and dynamically regulating cytokine receptor binding and function.

show abstract

High CD123 levels enhance proliferation in response to IL-3, but reduce chemotaxis by downregulating CXCR4 expression

Abstract: Key Points High CD123 expression increases proliferation and results in enhanced survival in response to low concentration of IL-3 in vitro. High CD123-expressing LSCs downregulate chemokine receptor expression, affecting niche interactions.

Cited by 27 publications

References 63 publications

41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo

41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo

Class C CpG Oligodeoxynucleotide Immunomodulatory Response in Aged Squirrel Monkey (Saimiri Boliviensis Boliviensis)

A dual role for the N-terminal domain of the IL-3 receptor in cell signalling

Contact Info

Product

Resources

About