Kallikrein-related peptidases protein expression in lymphoid tissues suggests potential implications in immune response

Filippou, Panagiota; Ren, Annie; Soosaipillai, Antoninus; Safar, Roaa; Prassas, Ioannis; Diamandis, Eleftherios P.; Conner, James

doi:10.1016/j.clinbiochem.2019.12.015

Cited by 7 publications

(4 citation statements)

References 48 publications

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“…These are singledomain serine proteases secreted as inactive zymogens (pro-KLKs). Under normal physiological conditions, KLKs are expressed in a variety of tissues with certain members displaying tissue-restricted patterns, whereas others having broad tissue expression patterns [136][137][138]. Reflecting their broad spectrum of tissue expression, KLKs are involved in a variety of biological processes and have been associated with several diseases such as cancer, inflammation and neurodegeneration [139].…”

Section: Inhibition Of Kallikrein-related Peptidase Activity 2211 Tissue Kallikrein Expression and Physiological Functionmentioning

confidence: 99%

Advances in understanding of Netherton syndrome and therapeutic implications

Petrova

Hovnanian

2020

Expert Opinion on Orphan Drugs

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Introduction: Netherton syndrome (NS) is a rare and severe ichthyosis characterized by superficial scaling, skin inflammation, a specific hair shaft defect, severe atopic manifestations and multisystemic complications. It is an orphan disease with currently no satisfactory treatment. NS is caused by loss-offunction mutations in SPINK5 encoding the serine protease inhibitor LEKTI. NS patients present with ichthyosiform erythroderma or ichthyosis linearis circumflexa and show considerable clinical variability. Areas covered: Uncontrolled serine protease activity leads to a profound skin barrier defect and the release of pro-inflammatory and pro-allergic mediators by keratinocytes and immune cells. Improved understanding of NS pathogenesis has led to the successful use of repurposed biologics such as intravenous immunoglobulins and anti-IL-17A blockers. Between April 1, 2020 and November 18, 2020, authors searched for NS-relevant information in the following databases: MEDLINE, DrugBank, ClinicalTrials.gov, and patent datasets accessed through lens.org. Expert opinion: Specific KLK5 and/or KLK7 inhibitors represent the most promising disease-modifying treatments. They are currently being developed by several companies. Comprehension of the determinants of NS variability, flares and modification over time will be the foundation for precision medicine. While improved knowledge of the inflammatory and allergic pathways involved is still needed, clinical trials using repurposed biologics have already begun.

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Section: Inhibition Of Kallikrein-related Peptidase Activity 2211 Tissue Kallikrein Expression and Physiological Functionmentioning

confidence: 99%

Advances in understanding of Netherton syndrome and therapeutic implications

Petrova

Hovnanian

2020

Expert Opinion on Orphan Drugs

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“…Kallikrein-related peptidases (KLKs) have been reported to possess novel functions in innate immunity and inflammation. KLK10 is expressed in the follicular dendritic cells that are essential for the maturation of B cells (40). KLK10 was dynamically regulated in T cells in vitro in response to viral antigens and in activated monocytes, pointing to its activities in the development of adaptive and innate immune function (41).…”

Section: Discussionmentioning

confidence: 99%

An estrogen response-related signature predicts response to immunotherapy in melanoma

Mei

Tang

et al. 2023

Front. Immunol.

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BackgroundEstrogen/estrogen receptor signaling influences the tumor microenvironment and affects the efficacy of immunotherapy in some tumors, including melanoma. This study aimed to construct an estrogen response-related gene signature for predicting response to immunotherapy in melanoma.MethodsRNA sequencing data of 4 immunotherapy-treated melanoma datasets and TCGA melanoma was obtained from open access repository. Differential expression analysis and pathway analysis were performed between immunotherapy responders and non-responders. Using dataset GSE91061 as the training group, a multivariate logistic regression model was built from estrogen response-related differential expression genes to predict the response to immunotherapy. The other 3 datasets of immunotherapy-treated melanoma were used as the validation group. The correlation was also examined between the prediction score from the model and immune cell infiltration estimated by xCell in the immunotherapy-treated and TCGA melanoma cases.Results“Hallmark Estrogen Response Late” was significantly downregulated in immunotherapy responders. 11 estrogen response-related genes were significantly differentially expressed between immunotherapy responders and non-responders, and were included in the multivariate logistic regression model. The AUC was 0.888 in the training group and 0.654–0.720 in the validation group. A higher 11-gene signature score was significantly correlated to increased infiltration of CD8+ T cells (rho=0.32, p=0.02). TCGA melanoma with a high signature score showed a significantly higher proportion of immune-enriched/fibrotic and immune-enriched/non-fibrotic microenvironment subtypes (p<0.001)–subtypes with better response to immunotherapy–and significantly better progression-free interval (p=0.021).ConclusionIn this study, we identified and verified an 11-gene signature that could predict response to immunotherapy in melanoma and was correlated with tumor-infiltrating lymphocytes. Our study suggests targeting estrogen-related pathways may serve as a combination strategy for immunotherapy in melanoma.

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“…In support of this hypothesis, it was shown that KLK6 is highly expressed in primary melanoma, which points to its involvement in the neoplastic processes and malignant progression 57 . As for KLK10 , it is expressed in the follicular dendritic cells that are essential for the maturation of B cells which suggest possible implications in the regulation of immune cells in lymphoid tissues 70 . As for the KLK10 gene, we found an overexpression in XP patients.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory landscape in Xeroderma pigmentosum patients with cutaneous melanoma

Chikhaoui

Jones

Režen

et al. 2022

Sci Rep

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Xeroderma pigmentosum (XP) is a DNA repair disease that predisposes to early skin cancers as cutaneous melanoma. Melanoma microenvironment contains inflammatory mediators, which would be interesting biomarkers for the prognosis or for the identification of novel therapeutic targets. We used a PCR array to evaluate the transcriptional pattern of 84 inflammatory genes in melanoma tumors obtained from XP patients (XP-Mel) and in sporadic melanoma (SP-Mel) compared to healthy skin. Commonly expressed inflammatory genes were further explored via GTEx and GEPIA databases. The differentially expressed inflammatory genes in XP were compared to their expression in skin exposed to UVs, and evaluated on the basis of the overall survival outcomes of patients with melanoma. Monocyte subsets of patients with SP-Mel, XP and healthy donors were also assessed. PCR array data revealed that 34 inflammatory genes were under-expressed in XP-Mel compared to SP-Mel. Differentially expressed genes that were common in XP-Mel and SP-Mel were correlated with the transcriptomic datasets from GEPIA and GTEx and highlighted the implication of KLK1 and IL8 in the tumorigenesis. We showed also that in XP-Mel tumors, there was an overexpression of KLK6 and KLK10 genes, which seems to be associated with a bad survival rate. As for the innate immunity, we observed a decrease of intermediate monocytes in patients with SP-Mel and in XP. We highlight an alteration in the immune response in XP patients. We identified candidate biomarkers involved in the tumorigenesis, and in the survival of patients with melanoma. Intermediate monocyte’s in patients at risk could be a prognostic biomarker for melanoma outcome.

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Kallikrein-related peptidases protein expression in lymphoid tissues suggests potential implications in immune response

Cited by 7 publications

References 48 publications

Advances in understanding of Netherton syndrome and therapeutic implications

Advances in understanding of Netherton syndrome and therapeutic implications

An estrogen response-related signature predicts response to immunotherapy in melanoma

Inflammatory landscape in Xeroderma pigmentosum patients with cutaneous melanoma

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