Assessment of cytotoxic T-lymphocyte phenotype using the specific markers granzyme B and TIA-1 in cervical neoplastic lesions

Bontkes, Hetty J.; Gruijl, Tanja D. de; Walboomers, Jan M. M.; Muysenberg, Adrie J.C. van den; Günther, Albrecht; Scheper, Rik J.; Meijer, C. J. L. M.; Kummer, J. Alain

doi:10.1038/bjc.1997.560

Cited by 48 publications

(40 citation statements)

References 36 publications

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“…The study of Bontkes et al (1997) gives some support to our findings. These authors analysed the proportion of activated CTLs and NK cells in cervical cancer and its prestages, by means of granzyme B staining, but they also did not find a correlation between granzyme B-expressing cells and the MHC class I expression in the tumours.…”

Section: Cytotoxic Activation Of Ctls and Nk Cells In Osccssupporting

confidence: 86%

Lack of MHC class I surface expression on neoplastic cells and poor activation of the secretory pathway of cytotoxic cells in oral squamous cell carcinomas

et al. 1999

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Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells use the secretory pathway of perforin/granzymes to kill their target cells. In contrast to NK cells, CTL responses are MHC class I restricted. In this study we analysed the relative activation of CTL and NK cells in relation with MHC class I expression on oral squamous cell carcinomas (OSCCs). MHC class I expression was investigated in 47 OSCCs by immunohistochemistry using HCA2, HC10 and β2-m antibodies. The presence of CTLs, NK cells, and its activation, was investigated in 21 of these OSCCs using respectively, CD8, CD57 and GrB7 antibodies. The Q-Prodit measuring system was used for quantification of cytotoxic cells. All OSCCs showed weak or absent staining of β2-m on the cell surface. The absence of β2-m was significantly associated with absent expression of MHC class I heavy chain as detected by HC10 antibody ( P = 0.004). In tumour infiltrates CTLs always outnumbered NK cells, as reflected by the ratio CD57/CD8 being always inferior to one (mean: 0.19; SD: 0.15). The proportion of activated cytotoxic cells as detected by granzyme B expression was generally low (mean: 8.6%; SD 8.9). A clear correlation between MHC class I expression and the relative proportion of NK cells/CTLs was not found. This study shows that the majority of OSCCs show weak or absent expression of MHC class I molecules on the cell surface, possibly due to alterations in the normal β2-m pathway. The low proportion of granzyme B-positive CTLs/NK cells indicates that the secretory pathway of cytotoxicity is poor in these patients. The lack of correlation between MHC class I expression and CTL/NK cell activation as detected by granzyme B expression suggests that, next to poor antigen presentation, also local factors seem to determine the final outcome of the cytotoxic immune response. © 1999 Cancer Research Campaign

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Section: Cytotoxic Activation Of Ctls and Nk Cells In Osccssupporting

confidence: 86%

Lack of MHC class I surface expression on neoplastic cells and poor activation of the secretory pathway of cytotoxic cells in oral squamous cell carcinomas

et al. 1999

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“…Previous studies have reported that HPVE7 affects the innate immune response by downregulating the expression of interferon-responsive genes, which affects activation of the subsequent adaptive immune response (18,19). Lymphocyte-mediated cytotoxicity involving cytotoxic T lymphocytes is the most effective mechanism for the control and clearance of viral infections (20,21). In the current study, PC3-E7 or CaSki-E7si cells were co-cultured with PBMCs, and the results demonstrated that HPV16E7 modulated lymphocyte proliferation and cytotoxic activity.…”

Section: Discussionsupporting

confidence: 50%

Increased expression of PD-L1 by the human papillomavirus 16 E7 oncoprotein inhibits anticancer immunity

Liu

Tian

et al. 2016

Mol Med Report

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Abstract. Cytotoxic T lymphocyte dysfunction is frequently associated with PD-L1/PD-1 pathway activation, and is a principal obstacle in cancer therapy. In the present study, the mechanisms underlying the human papillomavirus (HPV)-induced evasion of cervical cancer cells to the host immune system via the programmed death ligand 1/programmed death 1 (PD-L1/PD-1) signaling pathway was investigated. A significant increase in the expression of the HPV16E7 viral protein and PD-L1 in cervical tissues was observed when compared with normal cervical tissues. In addition, a positive correlation between HPV16E7 and PD-L1 expression was observed by immunohistochemical staining and reverse transcription-polymerase chain reaction. Overexpressing HPV16E7 oncoprotein in the epithelial carcinoma of PC3 cells increased the expression level of the PD-L1 protein and inhibited peripheral blood mononuclear cell (PBMC) proliferation and cytotoxic T lymphocyte (CTL) activity. Upon knockdown of HPV16E7 in HPV16-associated CaSki cervical cancer cells with a relevant siRNA, a reduction in PD-L1 protein expression was observed, as well as a significant increase in PBMC proliferation and CTL activity. A recombinant plasmid, MSCVPIG-soluble PD-1, was constructed and transfected into the CaSki cell line, and was co-cultured with PBMCs. PBMC proliferation and CTL activity were observed to increase significantly. In conclusion, the results presented in the current study suggest that overexpression of PD-L1, induced by HPV16E7, may be responsible for lymphocyte dysfunction. In addition, soluble PD-1 may restore the function of tumor-infiltrating lymphocytes by inhibiting the PD-L1/PD-1 signaling pathway. These results may provide a novel insight for immunotherapeutic approaches in the treatment of cervical cancer.

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“…Increased proportions of granzyme B ϩ / CD8 ϩ or granzyme B ϩ /CD3 ϩ lymphocytes have been detected in colorectal, renal, breast, and cervical carcinomas (range, 15-72%; Refs. 12,14,15,18).…”

Section: Discussionmentioning

confidence: 99%

“…The survival advantage of marked lymphocytic infiltration has been demonstrated in patients with malignant melanoma; colorectal, esophageal, and cervical carcinoma; medullary carcinoma of the breast; and epithelial ovarian cancer (12,14,15,17,21,22). In contrast, the presence of activated CTLs correlated positively with aggressive disease and with reduced overall survival in patients with Hodgkin's or non-Hodgkin's lymphoma (23,24), and more abundant infiltration of tumor tissue by CTLs was associated with shorter survival in patients with renal cell carcinoma (18).…”

Section: Discussionmentioning

confidence: 99%

“…Natural killer cells are virtually absent in endometrial tumors (11). Activated CTLs expressing TIA-1 and/or granzyme B cytotoxic granules have been demonstrated in certain human neoplasms, such as EBV-associated gastric cancer, medullary carcinoma of the breast, germ cell tumors of the testis, and carcinomas of the colon, cervix, esophagus, and kidney (12)(13)(14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Intratumoral CD8+ T Lymphocytes as a Prognostic Factor of Survival in Endometrial Carcinoma

Kondratiev¹,

Sabo²,

Yakirevich³

et al. 2004

Clinical Cancer Research

191

141

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Results: Patients with >10 CD8 ؉ T lymphocytes/highpower field within the tumor epithelium at the invasive border displayed improved overall survival compared with patients with fewer intraepithelial CD8 ؉ T lymphocytes (87 and 50%, respectively; P ‫؍‬ 0.027). Multivariate analysis revealed that stage, vascular invasion, grade, and the number of intraepithelial CD8؉ T lymphocytes at the invasive border were the only independent predictors of survival (P < 0.0001, P ‫؍‬ 0.001, P ‫؍‬ 0.011, and P ‫؍‬ 0.025, respectively). Granzyme B ؉ cytoplasmatic granules were detected in a high proportion of CTLs, confirming their activated cytotoxic phenotype.Conclusions: Our study demonstrates for the first time that increased numbers of CTLs at the invasive border may be a reliable independent prognostic factor of survival in patients with endometrial carcinoma.

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Assessment of cytotoxic T-lymphocyte phenotype using the specific markers granzyme B and TIA-1 in cervical neoplastic lesions

Cited by 48 publications

References 36 publications

Lack of MHC class I surface expression on neoplastic cells and poor activation of the secretory pathway of cytotoxic cells in oral squamous cell carcinomas

Lack of MHC class I surface expression on neoplastic cells and poor activation of the secretory pathway of cytotoxic cells in oral squamous cell carcinomas

Increased expression of PD-L1 by the human papillomavirus 16 E7 oncoprotein inhibits anticancer immunity

Intratumoral CD8+ T Lymphocytes as a Prognostic Factor of Survival in Endometrial Carcinoma

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