Defective γδ T-cell function and granzyme B gene polymorphism in a cohort of newly diagnosed breast cancer patients

Gaafar, Ameera; Aljurf, Mahmoud; Al-Sulaiman, Abdullah; Iqniebi, Alia; Manogaran, Pulicat; Mohamed, Gamal El-Din; Alsayed, Adher; Alzahrani, Hazaa; Alsharif, Fahad; Mohareb, Fahad Al; Ajarim, Dahish; Tabakhi, Abdelghani; Al-Hussein, Khalid

doi:10.1016/j.exphem.2009.04.003

Cited by 46 publications

(36 citation statements)

References 39 publications

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“…The first report (McIlroy et al, 2003) describing significantly reduced cytotoxicity of a granzyme B morphant encoded by the Q48R, P88A, Y245H allele was later contradicted by a study using a more physiological relevant model (delivering gzmB via perforin and not expressing it in the target cell; Sun et al, 2004), showing that RAH granzyme B retains its apoptotic potential. Whether the RAH polymorphism decreases gzmB expression levels (McIlroy et al, 2003;Gaafar et al, 2009;Girnita et al, 2009) is still a matter for debate, although it was shown that CTLs and NKs are not impaired in their killing potential (Sun et al, 2004;Zaitsu et al, 2004) but γδ T cells are (Gaafar et al, 2009). Studies linking gzmB polymorphisms with disease are yielding inconsistent results: for example, the QPY allele is linked to Epstein Barr virusassociated hemophagocytic lymphohistiocytosis (Zaitsu et al, 2004) but not familial hemophagocytic lymphohistiocytosis (Ericson et al, 2003).…”

Section: Granzyme Gene Polymorphismsmentioning

confidence: 94%

Are all granzymes cytotoxicin vivo?

Joeckel

Bird

2014

Biological Chemistry

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Granzymes are serine proteases mainly found in cytotoxic lymphocytes. The most-studied member of this group is granzyme B, which is a potent cytotoxin that has set the paradigm that all granzymes are cyototoxic. In the last 5 years, this paradigm has become controversial. On one hand, there is a plethora of sometimes contradictory publications showing mainly caspase-independent cytotoxic effects of granzyme A and the so-called orphan granzymes in vitro. On the other hand, there are increasing numbers of reports of granzymes failing to induce cell death in vitro unless very high (potentially supra-physiological) concentrations are used. Furthermore, experiments with granzyme A or granzyme M knock-out mice reveal little or no deficit in their cytotoxic lymphocytes' killing ability ex vivo, but indicate impairment in the inflammatory response. These findings of non-cytotoxic effects of granzymes challenge dogma, and thus require alternative or additional explanations to be developed of the role of granzymes in defeating pathogens. Here we review evidence for granzyme cytotoxicity, give an overview of their non-cytotoxic functions, and suggest technical improvements for future investigations.

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Section: Granzyme Gene Polymorphismsmentioning

confidence: 94%

Are all granzymes cytotoxicin vivo?

Joeckel

Bird

2014

Biological Chemistry

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“…34 Deficient gd T cell functions have already been observed in various malignancies, including hematological, 20 liver, 35 breast 35 and gastric cancers. 36 Re-establishment of gd T cell antitumor activity is therefore valuable.…”

Section: Gd T Cells and Cancer Immunitymentioning

confidence: 99%

Empowering gamma delta T cells with antitumor immunity by dendritic cell-based immunotherapy

Anguille

et al. 2015

OncoImmunology

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These authors equally contributed to the work.Keywords: gd T cell, cancer, DC-mediated gd T cell activation, dendritic cell, immunotherapy Abbreviations: gd, gamma delta; BCG, Bacillus Calmette-Guerin; BrHPP, bromohydrin pyrophosphate; CTL, cytotoxic T lymphocyte; DC, dendritic cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; HIV, human immunodeficiency virus; HMBPP, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate; iDC, immature DC; IFN, interferon; IL, interleukin; IPP, isopentyl pyrophosphate; mDC, myeloid dendritic cell; MHC, major histocompatibility complex; mo-DC, monocyte-derived dendritic cell; pDC, plasmacytoid dendritic cell; PD, programmed cell death protein; TCR, T-cell receptor; Th, T-helper cell; TLR, toll-like receptor; TNF, tumor necrosis factor; Treg, regulatory T cellGamma delta (gd) T cells are the all-rounders of our immune-system with their major histocompatibility complexunrestricted cytotoxicity, capacity to secrete immunostimulatory cytokines and ability to promote the generation of tumor antigen-specific CD8 C and CD4 C T cell responses. Dendritic cell (DC)-based vaccine therapy has the prospective to harness these unique features of the gd T cells in the fight against cancer. In this review, we will discuss our current knowledge on DC-mediated gd T cell activation and related opportunities for tumor immunologists.

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“…Moreover, the RAH haplotype was associated with a predisposition to develop breast cancer. People presenting genotype RAH/RAH were 16 times more likely to have breast cancer as compared with those with genotype QPY/QPY, and individuals with the wild-type QPY/QPY displayed higher cytotoxicity against tumor cell lines, in comparison to donors with the mutated type RAH/RAH 19 .…”

Section: Discussionmentioning

confidence: 98%

Distribution of QPY and RAH haplotypes of granzyme B gene in distinct Brazilian populations

Garcia

Kashima

Rodrigues

et al. 2012

Rev. Soc. Bras. Med. Trop.

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Introduction:The cytolysis mediated by granules is one of the most important effector functions of cytotoxic T lymphocytes and natural killer cells. Recently, three single nucleotide polymorphisms (SNPs) were identified at exons 2, 3, and 5 of the granzyme B gene, resulting in a haplotype in which three amino acids of mature protein Q48P88Y245 are changed to R48A88H245, which leads to loss of cytotoxic activity of the protein. In this study, we evaluated the frequency of these polymorphisms in Brazilian populations. Methods: We evaluated the frequency of these polymorphisms in Brazilian ethnic groups (white, Afro-Brazilian, and Asian) by sequencing these regions. Results: The allelic and genotypic frequencies of SNP 2364A/G at exon 2 in Afro-Brazilian individuals (42.3% and 17.3%) were significantly higher when compared with those in whites and Asians (p < 0.0001 and p = 0.0007, respectively). The polymorphisms 2933C/G and 4243C/T also were more frequent in Afro-Brazilians but without any significant difference regarding the other groups. The Afro-Brazilian group presented greater diversity of haplotypes, and the RAH haplotype seemed to be more frequent in this group (25%), followed by the whites (20.7%) and by the Asians (11.9%), similar to the frequency presented in the literature. Conclusions: There is a higher frequency of polymorphisms in Afro-Brazilians, and the RAH haplotype was more frequent in these individuals. We believe that further studies should aim to investigate the correlation of this haplotype with diseases related to immunity mediated by cytotoxic lymphocytes, and if this correlation is confirmed, novel treatment strategies might be elaborated.

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Defective γδ T-cell function and granzyme B gene polymorphism in a cohort of newly diagnosed breast cancer patients

Cited by 46 publications

References 39 publications

Are all granzymes cytotoxicin vivo?

Are all granzymes cytotoxicin vivo?

Empowering gamma delta T cells with antitumor immunity by dendritic cell-based immunotherapy

Distribution of QPY and RAH haplotypes of granzyme B gene in distinct Brazilian populations

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