A novel role for an old target: CD45 for breast cancer immunotherapy

Raiter, Annat; Zlotnik, Oran; Lipovetsky, Julia; Dar, Shir; Lubin, Ido; Sharon, Eran; Cohen, Cyrille J.; Yerushalmi, Rinat

doi:10.1080/2162402x.2021.1929725

Cited by 16 publications

(15 citation statements)

References 53 publications

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“…Similar to our findings on TNBC tumors ( 8 ), viral interference with the functions of the receptor tyrosine phosphatase CD45 have been widely reported. It was demonstrated that CD45 functions are crucial for stimulating a protective immune response against Herpes simplex virus type 1 (HSV-1) ( 29 ).…”

Section: Discussionsupporting

confidence: 92%

“…We recently reported an immune escape mechanism in TNBC patients showing that CD45's intracellular signals are inhibited ( 8 ). We also reported that C24D, a previously described immune modulating therapeutic peptide ( 9 ), binds to the CD45 receptor of the TNBC-suppressed immune cells and reverses immune-suppression, via the CD45 signaling pathway ( 8 ). C24D-binding to CD45 in the immune-suppressed cells resulted in immune reactivation and specific tumor killing.…”

Section: Introductionmentioning

confidence: 99%

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Downregulation of CD45 Signaling in COVID-19 Patients Is Reversed by C24D, a Novel CD45 Targeting Peptide

et al. 2021

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CD45, the predominant transmembrane tyrosine phosphatase in leukocytes, is required for the efficient induction of T cell receptor signaling and activation. We recently reported that the CD45-intracellular signals in peripheral blood mononuclear cells (PBMCs) of triple negative breast cancer (TNBC) patients are inhibited. We also reported that C24D, an immune modulating therapeutic peptide, binds to CD45 on immune-suppressed cells and resets the functionality of the immune system via the CD45 signaling pathway. Various studies have demonstrated that also viruses can interfere with the functions of CD45 and that patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are immune-suppressed. Given the similarity between the role of CD45 in viral immune suppression and our findings on TNBC, we hypothesized that the C24D peptide may have a similar “immune-resetting” effect on PBMCs from COVID-19 patients as it did on PBMCs from TNBC patients. We tested this hypothesis by comparing the CD45/TCR intracellular signaling in PBMCs from ten COVID-19 patients vs. PBMCs from ten healthy volunteers. Herein, we report our findings, demonstrating the immune reactivating effect of C24D via the phosphorylation of the tyrosine 505 and 394 in Lck, the tyrosine 493 in ZAP-70 and the tyrosine 172 in VAV-1 proteins in the CD45 signaling pathway. Despite the relatively small number of patients in this report, the results demonstrate that C24D rescued CD45 signaling. Given the central role played by CD45 in the immune system, we suggest CD45 as a potential therapeutic target.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Downregulation of CD45 Signaling in COVID-19 Patients Is Reversed by C24D, a Novel CD45 Targeting Peptide

et al. 2021

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“…In addition, it has been reported that CD45 is the receptor of CD24D, and the immunomodulatory peptide CD24D can reverse the immunosuppression induced by TNBC by activating the CD45 signaling pathway, and participate in the biological process of immunomodulatory tumor cell killing. CD45 may be the target of TNBC immune response recovery ( Raiter et al, 2021 ). In conclusion, we believe that even though these five hub genes are not all expressed on macrophages, they can all play a role through macrophages, which also demonstrates the accuracy of them as macrophage-related genes.…”

Section: Discussionmentioning

confidence: 99%

Establishment and validation of an individualized macrophage-related gene signature to predict overall survival in patients with triple negative breast cancer

Peng

et al. 2021

PeerJ

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Background Recently, researchers have classified highly heterogeneous triple negative breast cancer (TNBC) into different subtypes from different perspectives and investigated the characteristics of different subtypes to pursue individualized treatment. With the increase of immunotherapy and its preliminary application in TNBC treatment, the value of immune-related strategies in the treatment of TNBC has been initially reflected. Based thereon, this study plans to classify and further explore TNBC from the perspective of immune cell infiltration. Method The fractions of immune cells of TNBC patients were assessed by six immune component analysis methods in The Cancer Genome Atlas (TCGA) database. Hub genes significantly related to poor prognosis were verified by weighted gene co-expression network analysis (WGCNA) analysis, Lasso analysis, and univariate KM analysis. Two cohorts of TNBC patients with complete prognosis information were collected for validation analysis. Finally, the Genomics of Drug Sensitivity in Cancer (GDSC) database was adopted to ascertain the sensitivity differences of different populations based on hub-gene grouping to different chemotherapy drugs. Results Five hub genes (CD79A, CXCL13, IGLL5, LHFPL2, and PLEKHF1) of the key co-expression gene module could divide TNBC patients into two groups (Cluster A and Cluster B) based on consistency cluster analysis. The patients with Cluster A were responsible for significantly worse prognosis than the patients with Cluster B (P = 0.023). In addition, another classification method, PCoA, and two other datasets (GSE103091 and GSE76124), were used to obtain consistent results with previous findings, which verified the stability of the classification method and dataset in this study. The grouping criteria based on the previous results were developed and the accuracy of the cut-off values was validated. A prognosis model of TNBC patients was then constructed based on the grouping results of five hub genes and N staging as prognostic factors. The results of ROC and decision curve analyses showed that this model had high prediction accuracy and patients could benefit therefrom. Finally, GDSC database analysis proved that patients in Cluster A were more sensitive to Vinorelbine. Separate analysis of the sensitivity of patients in Cluster A to Gemcitabine and Vinorelbine showed that the patients in Cluster A exhibited higher sensitivity to Vinorelbine. We hypothesized that these five genes were related to gemcitabine resistance and they could serve as biomarkers for clinical drug decision-making after anthracene resistance and taxane resistance in patients with advanced TNBC. Conclusion This study found five hub prognostic genes associated with macrophages, and a prognostic model was established to predict the survival of TNBC patients. Finally, these five genes were related to gemcitabine resistance in TNBC patients.

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“…The former is associated with immune disorders including autoimmune hepatitis, HIV infection, and multiple sclerosis, while A138G is associated with hepatitis B, Graves´ disease, and severe combined immunodeficiency [ 16 , 17 , 18 ]. Furthermore, CD45 has been shown to be involved in tumor-induced immunosuppression in peripheral blood mononuclear cells [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…In an initial experiment, we demonstrated that LPS increases CD45 expression of granulocytes, lymphocytes, and monocytes. We therefore decided to study: (1) the ex vivo effect of LPS in volunteers, (2) the CD45 expression in an inflammatory disease (COVID- 19), and (3) the eventual differences in LPS-induced CD45 expression in volunteers and COVID-19 patients.…”

Section: Introductionmentioning

confidence: 99%

Differential Regulation of CD45 Expression on Granulocytes, Lymphocytes, and Monocytes in COVID-19

Ahmed

Limmer

Sucker

et al. 2022

JCM

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CD45 is a transmembrane glycoprotein and protein tyrosine phosphatase expressed on the surface of all nucleated hematopoietic cells. While there is increasing evidence demonstrating the involvement of CD45 in immune system regulation, no information on CD45 expression in inflammation and sepsis is currently available. Therefore, we determined the CD45 surface expression on granulocytes, lymphocytes, and monocytes in patients with COVID-19 and healthy volunteers in both absence and presence of lipopolysaccharide (LPS). Following approval by the local ethics committee, whole blood samples were obtained from patients with COVID-19 infection on day 1 of hospital admission and healthy volunteers. Samples were incubated in absence and presence of LPS and CD45 was measured in granulocytes, lymphocytes, and monocytes using flow cytometry. In comparison with healthy individuals, COVID-19 patients showed an increased CD45 expression on the surface of granulocytes (+35%, p < 0.02) and lymphocytes (+39%, p < 0.0001), but a reduced CD45 expression on monocytes (−35%, p < 0.0001). LPS incubation of whole blood from healthy individuals increased the CD45 expression on granulocytes (+430%, p < 0.0001), lymphocytes (+32%, p = 0.0012), and monocytes (+36%, p = 0.0005), respectively. LPS incubation of whole blood samples from COVID-19 patients increased the CD45 expression on granulocytes and monocytes, and decreased the CD45 expression on lymphocytes. In conclusion, CD45 expression on leucocytes is altered: (1) in COVID-19 patients, and (2) in in vitro endotoxemia in a complex cell-specific way, thus representing a new immunoregulatory mechanism.

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A novel role for an old target: CD45 for breast cancer immunotherapy

Cited by 16 publications

References 53 publications

Downregulation of CD45 Signaling in COVID-19 Patients Is Reversed by C24D, a Novel CD45 Targeting Peptide

Downregulation of CD45 Signaling in COVID-19 Patients Is Reversed by C24D, a Novel CD45 Targeting Peptide

Establishment and validation of an individualized macrophage-related gene signature to predict overall survival in patients with triple negative breast cancer

Differential Regulation of CD45 Expression on Granulocytes, Lymphocytes, and Monocytes in COVID-19

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