Specific Immune Response and Cytokine Production in CD70 Deficiency

Abolhassani, Hassan

doi:10.3389/fped.2021.615724

Cited by 8 publications

(7 citation statements)

References 72 publications

(90 reference statements)

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“…This indicates that silencing of CD70 may be a viable option for overcoming CD70CAR-T fratricide, improving viability of CD70CAR-T cells. However, as recent investigation noted the impact of CD70 deficiency on the function of CD8 T cells, 100 the possibility of selectively expanding CD4+ CAR-T cells, already shown to be more effective against GBM, 101 would be even more relevant.…”

Section: Resultsmentioning

confidence: 99%

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CD70 as an actionable immunotherapeutic target in recurrent glioblastoma and its microenvironment

Seyfrid

Maich

Shaikh

et al. 2022

J Immunother Cancer

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PurposeGlioblastoma (GBM) patients suffer from a dismal prognosis, with standard of care therapy inevitably leading to therapy-resistant recurrent tumors. The presence of cancer stem cells (CSCs) drives the extensive heterogeneity seen in GBM, prompting the need for novel therapies specifically targeting this subset of tumor-driving cells. Here, we identify CD70 as a potential therapeutic target for recurrent GBM CSCs.Experimental designIn the current study, we identified the relevance and functional influence of CD70 on primary and recurrent GBM cells, and further define its function using established stem cell assays. We use CD70 knockdown studies, subsequent RNAseq pathway analysis, and in vivo xenotransplantation to validate CD70’s role in GBM. Next, we developed and tested an anti-CD70 chimeric antigen receptor (CAR)-T therapy, which we validated in vitro and in vivo using our established preclinical model of human GBM. Lastly, we explored the importance of CD70 in the tumor immune microenvironment (TIME) by assessing the presence of its receptor, CD27, in immune infiltrates derived from freshly resected GBM tumor samples.ResultsCD70 expression is elevated in recurrent GBM and CD70 knockdown reduces tumorigenicity in vitro and in vivo. CD70 CAR-T therapy significantly improves prognosis in vivo. We also found CD27 to be present on the cell surface of multiple relevant GBM TIME cell populations, notably putative M1 macrophages and CD4 T cells.ConclusionCD70 plays a key role in recurrent GBM cell aggressiveness and maintenance. Immunotherapeutic targeting of CD70 significantly improves survival in animal models and the CD70/CD27 axis may be a viable polytherapeutic avenue to co-target both GBM and its TIME.

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Section: Resultsmentioning

confidence: 99%

“…Limiting dilution analysis GBM cells (CD70+/CD70-or Control/CD70 Knockout cells) were plated at varying densities (1,3,5,10,15,25,50,75,100,125,150, 200 cells/well) were flow-sorted onto a low-binding 96-well plate. Cells were cultured in 200 µL of media and incubated for 4 days at 37°C and 5% CO 2 .…”

Section: Glycocapture Proteomicsmentioning

confidence: 99%

CD70 as an actionable immunotherapeutic target in recurrent glioblastoma and its microenvironment

Seyfrid

Maich

Shaikh

et al. 2022

J Immunother Cancer

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“… 60 Defects in the CD27–CD70 axis indicate an immunodeficiency associated with terminal B-cell development defect and immune dysregulation leading to autoimmunity, uncontrolled viral infection, and lymphomas. 61 …”

Section: Resultsmentioning

confidence: 99%

SARS-CoV-2-Induced Immunosuppression: A Molecular Mimicry Syndrome

Kanduc

2022

Glob Med Genet

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Background Contrary to immunological expectations, decay of adaptive responses against severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) characterizes recovered patients compared with patients who had a severe disease course or died following SARS-CoV-2 infection. This raises the question of the causes of the virus-induced immune immunosuppression. Searching for molecular link(s) between SARS-CoV-2 immunization and the decay of the adaptive immune responses, SARS-CoV-2 proteome was analyzed for molecular mimicry with human proteins related to immunodeficiency. The aim was to verify the possibility of cross-reactions capable of destroying the adaptive immune response triggered by SARS-CoV-2. Materials and Methods Human immunodeficiency–related proteins were collected from UniProt database and analyzed for sharing of minimal immune determinants with the SARS-CoV-2 proteome. Results Molecular mimicry and consequent potential cross-reactivity exist between SARS-CoV-2 proteome and human immunoregulatory proteins such as nuclear factor kappa B (NFKB), and variable diversity joining V(D)J recombination-activating gene (RAG). Conclusion The data (1) support molecular mimicry and the associated potential cross-reactivity as a mechanism that can underlie self-reactivity against proteins involved in B- and T-cells activation/development, and (2) suggest that the extent of the immunosuppression is dictated by the extent of the immune responses themselves. The higher the titer of the immune responses triggered by SARS-CoV-2 immunization, the more severe can be the cross-reactions against the human immunodeficiency–related proteins, the more severe the immunosuppression. Hence, SARS-CoV-2-induced immunosuppression can be defined as a molecular mimicry syndrome. Clinically, the data imply that booster doses of SARS-CoV-2 vaccines may have opposite results to those expected.

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“…Additionally, the present study revealed that CD27 and CD70 gene expression was significantly lower in the non-lesional areas compared to HCs. Interestingly, Abolhassani [ 23 ] reported two family members with genetic abnormalities in the CD70- CD27 signaling cascade associated with clinical features of AA, Behcet's disease, recurrent viral pneumonia, central nervous system infection, and Hodgkin lymphoma induced by Epstein–Barr virus. The patients' clinical and immunologic data revealed an abnormality in B-cell differentiation, impaired functional activity of effector T cells, and decreased antibody production, which increased vulnerability to recurrent viral illness.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression of CD70 and CD27 Is Increased in Alopecia Areata Lesions and Associated with Disease Severity and Activity

Marie

El‐Fadeal

Marei

et al. 2022

Dermatology Research and Practice

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Background. Alopecia areata (AA) is an acquired hair loss disorder induced by a cell-mediated autoimmune attack against anagen hair follicles. CD27-CD70 is a receptor-ligand complex which enhances T helper and cytotoxic T cell activation, survival, and proliferation. The overstimulation of this complex can lead to a lack of tolerance and the development of autoimmunity. Objectives. This study aimed to assess the gene expression of CD27 and CD70 in patients with AA. Methods. CD70 and CD27 mRNA expressions were evaluated by a quantitative real-time polymerase chain reaction in scalp biopsies from 40 AA patients (both AA lesions and non-lesional areas) and 40 healthy controls (HCs). The Severity of Alopecia Tool (SALT) score was used to assess AA severity. Patients were evaluated for signs of AA activity, including a positive hair pull test and dermoscopic features of black dots, broken hairs, and tapering hairs. Results. The gene expression of CD70 and CD27 was significantly higher in AA lesions than in non-lesional areas ( p < 0.001 for both) and HCs ( p = 0.004 , p = 0.014 , respectively). There were significant positive correlations between AA severity and gene expression of CD70 ( p < 0.001 ) and CD27 ( p = 0.030 ) in AA lesions. Significant associations were detected between signs of AA activity and lesional gene expression of CD70 and CD27. Additionally, CD70 and CD27 gene expression was significantly lower in non-lesional biopsies compared to HCs ( p < 0.001 ). Conclusion. Gene expression of CD70 and CD27 was increased in AA lesions and was associated with disease severity and activity. Thus, both molecules can be a predictor of AA severity and activity. Furthermore, the expression was reduced in non-lesional scalp areas. Thus, a lack of CD27 and CD70 expression may initially predispose to immunological dysregulation and the development of AA.

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Specific Immune Response and Cytokine Production in CD70 Deficiency

Cited by 8 publications

References 72 publications

CD70 as an actionable immunotherapeutic target in recurrent glioblastoma and its microenvironment

CD70 as an actionable immunotherapeutic target in recurrent glioblastoma and its microenvironment

SARS-CoV-2-Induced Immunosuppression: A Molecular Mimicry Syndrome

Gene Expression of CD70 and CD27 Is Increased in Alopecia Areata Lesions and Associated with Disease Severity and Activity

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