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Lung carcinomas do not induce T-cell apoptosis via the Fas/Fas ligand pathway but down-regulate CD3 epsilon expression

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Abstract

Background

Non-small cell lung carcinoma (NSCLC) patients have impaired cellular immune responses. It has been hypothesized that tumor cells expressing Fas Ligand (FasL) induce in T lymphocytes: (a) apoptosis (tumor counterattack) and (b) down-regulation of CD3ζ expression. However, the hypothesis of tumor counterattack is still controversial.

Methods

We analyzed FasL expression on NSCLC cell lines and on tumor cells from lung adenocarcinoma patients by flow cytometry and immunocytochemistry. FasL mRNA expression was detected in NSCLC cell lines using RT-PCR, and functional FasL was evaluated on Fas-expressing Jurkat T-cells by annexin-V-FITC staining and by SubG1 peak detection. Also, the proapoptotic effect of microvesicles released from NSCLC cell lines in Jurkat T-cells was studied. Alterations in the expression levels of CD3ζ, CD3ε, and CD28 [measured as mean fluorescence intensity (MFI)] were determined in Jurkat T-cells after co-culture with NSCLC cell lines or tumor-derived microvesicles. Furthermore, the expression levels of CD3ζ and CD3ε in CD4+T and CD8+T lymphocytes from lung adenocarcinoma patients was studied.

Results

Our results indicate that NSCLC cells neither FasL expressed nor induced apoptosis in Jurkat T-cells. Tumor-derived microvesicles did not induce apoptosis in Jurkat T-cells. In contrast, NSCLC cell lines down-regulated CD3ε but not CD3ζ chain expression in Jurkat T-cells; this effect was induced by soluble factors but not by microvesicles. In lung adenocarcinoma patients, significant decreases of MFI values for CD3ε, but not CD3ζ, were found in CD4+T and CD8+T cells from pleural effusion compared to peripheral blood and in peripheral blood of patients compared to healthy donors.

Conclusions

Our data do not support the tumor counterattack hypothesis for NSCLC. Nonetheless, down-regulation of CD3ε in T-cells induced by NSCLC cells might lead to T-cell dysfunction.

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Acknowledgments

This work was supported by CONACYT grants F643-M9406 and 46389-M.

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Authors and Affiliations

  1. Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Tlalpan 4502, Col. Seccion XVI, CP 14080, Mexico City, Mexico

    Heriberto Prado-Garcia, Dolores Aguilar-Cazares, Manuel Meneses-Flores & Jose Sullivan Lopez-Gonzalez

  2. Servicio Clinico 3, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Tlalpan 4502, Col. Seccion XVI, CP 14080, Mexico City, Mexico

    Jorge Morales-Fuentes

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  1. Heriberto Prado-Garcia
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  2. Dolores Aguilar-Cazares
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  5. Jose Sullivan Lopez-Gonzalez
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Correspondence to Jose Sullivan Lopez-Gonzalez.

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Prado-Garcia, H., Aguilar-Cazares, D., Meneses-Flores, M. et al. Lung carcinomas do not induce T-cell apoptosis via the Fas/Fas ligand pathway but down-regulate CD3 epsilon expression. Cancer Immunol Immunother 57, 325–336 (2008). https://doi.org/10.1007/s00262-007-0372-6

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