Emerging Canonical and Non-Canonical Roles of Granzyme B in Health and Disease

Tibbs, Ellis; Cao, Xuefang

doi:10.3390/cancers14061436

Cited by 24 publications

(18 citation statements)

References 109 publications

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“…The most significant transcriptional differences were observed in CD4+ T (central memory and naïve), CD8+ T (transitional and naïve), monocytes (classic, non-classic and NKG7 high), and migratory myeloid and macrophage M1-like cells ( Figure 3C ). In high metastatic disease, the lymphoid populations CD4+ and CD8+ T cells show upregulation of GZMK (pro-inflammatory) [25] and downregulation of GZMB and GNLY (cytolytic activity) [26] [27]. However, NK cells in high metastatic disease are marked by relatively lower expression of S100A8, a pro-inflammatory factor that promotes metastasis [28, 29].…”

Section: Resultsmentioning

confidence: 99%

The circulating immune cell landscape stratifies metastatic burden in breast cancer patients

Mangiola,

Brown,

Berthelet

et al. 2023

Preprint

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Advanced breast cancers show varying degrees of metastasis; however, reliable biomarkers of metastatic disease progression remain unknown. In circulation, immune cells are the first line of defence against tumour cells. Herein, using >109,591 peripheral blood mononuclear cells from healthy individuals and breast cancer patients, we tested whether molecular traits of the circulating immune cells, probed with single-cell transcriptomics, can be used to segregate metastatic profiles. Our analyses revealed significant compositional and transcriptional differences in PBMCs of patients with restricted or high metastatic burden versus healthy subjects. The abundance of T cell and monocyte subtypes segregated cancer patients from healthy individuals, while memory and unconventional T cells were enriched in low metastatic burden disease. The cell communication axes were also found to be tightly associated with the extent of metastatic burden. Additionally, we identified a PBMC-derived metastatic gene signature capable of discerning metastatic condition from a healthy state. Our study provides unique molecular insights into the peripheral immune system operating in metastatic breast cancer, revealing potential new biomarkers of the extent of the metastatic state. Tracking such immune traits associated with metastatic spread could complement existing diagnostic tools.

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Section: Resultsmentioning

confidence: 99%

The circulating immune cell landscape stratifies metastatic burden in breast cancer patients

Mangiola,

Brown,

Berthelet

et al. 2023

Preprint

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“…CD69 is one of the early T cell activation markers (35,36) while GZMB gene product granzyme B is expressed in matured T cells inducing a killer phenotype (42). ZFP36 is a newly characterized master regulator of T cell activation controlling post transcriptional regulation.…”

Section: Discussionmentioning

confidence: 99%

An approach of scoring early host immune response from oro-nasopharyngeal swabs predicts covid-19 outcome providing possibility of early therapeutic intervention

Pal,

Rajput,

Neral

et al. 2023

Preprint

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Unpredictable fatal outcome of COVID-19 is attributed to dysregulated inflammation. The purpose of this study was to develop biomarkers for early detection of host immune impairment which may in turn identify high risk patients. We used RT-PCR to evaluate if impaired anti-inflammatory response (as defined by undetectable IL-10 in the presence of high expression of a representative interferon response gene) and/or impaired adaptive T cell response, assessed in leftover RNA samples extracted from oro-nasopharyngeal swab of COVID-19 patients at diagnosis, could serve as early prognostic marker/s. We demonstrate that a T cell response based ‘severity score’ comprising rational combination of Ct values of target genes can identify high risk noncomorbid potentially critical COVID-19 patients with a sensitivity of 91% (95% CI:58.7-99.8) and specificity of 92.6% (95% CI:75.7-99). Although inclusion of co-morbid patients reduced sensitivity to 77% (95% CI: 54.6-92.2), the specificity was still 94% (95% CI: 79.8-99.3). The work flow developed in the same pipeline of the COVID-19 diagnostic samples can also reduce expenditure and reporting time of the test for an earliest clinical decision ensuring possibility of early prophylactic treatment and rational management of patients.

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“…In this way plasmin could facilitate matrix degradation during various physiological and pathological events ( 140 ). Another example of cross-class activation is when the serine protease granzymes, released by cytotoxic T cells or natural killer cells, initiate the apoptosis by activating the cysteine protease caspases in the target cells ( 141 ). The discovery that a proprotein convertase is involved in the alternative pathway activation drew attention to the cooperation between the proprotein convertases and the complement system ( Figure 5 ).…”

Section: Discussionmentioning

confidence: 99%

Proprotein Convertases and the Complement System

et al. 2022

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Proteins destined for secretion - after removal of the signal sequence - often undergo further proteolytic processing by proprotein convertases (PCs). Prohormones are typically processed in the regulated secretory pathway, while most plasma proteins travel though the constitutive pathway. The complement system is a major proteolytic cascade in the blood, serving as a first line of defense against microbes and also contributing to the immune homeostasis. Several complement components, namely C3, C4, C5 and factor I (FI), are multi-chain proteins that are apparently processed by PCs intracellularly. Cleavage occurs at consecutive basic residues and probably also involves the action of carboxypeptidases. The most likely candidate for the intracellular processing of complement proteins is furin, however, because of the overlapping specificities of basic amino acid residue-specific proprotein convertases, other PCs might be involved. To our surprise, we have recently discovered that processing of another complement protein, mannan-binding lectin-associated serine protease-3 (MASP-3) occurs in the blood by PCSK6 (PACE4). A similar mechanism had been described for the membrane protease corin, which is also activated extracellularly by PCSK6. In this review we intend to point out that the proper functioning of the complement system intimately depends on the action of proprotein convertases. In addition to the non-enzymatic components (C3, C4, C5), two constitutively active complement proteases are directly activated by PCs either intracellularly (FI), or extracellularly (MASP-3), moreover indirectly, through the constitutive activation of pro-factor D by MASP-3, the activity of the alternative pathway also depends on a PC present in the blood.

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Emerging Canonical and Non-Canonical Roles of Granzyme B in Health and Disease

Cited by 24 publications

References 109 publications

The circulating immune cell landscape stratifies metastatic burden in breast cancer patients

The circulating immune cell landscape stratifies metastatic burden in breast cancer patients

An approach of scoring early host immune response from oro-nasopharyngeal swabs predicts covid-19 outcome providing possibility of early therapeutic intervention

Proprotein Convertases and the Complement System

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