Abstract
The use of antineoplastic drugs for cancer treatment is frequently associated with the acquisition of a multidrug-resistant (MDR) phenotype that renders tumoural cells insensitive to antineoplastics. It remains elusive whether the acquisition of the MDR phenotype alters immunological parameters that could influence the cell sensitivity to an eventual host immune response. We report that immunisation of syngeneic mice with γ-irradiated L1210S (parental line) and L1210R (MDR phenotype) cells results in a significant rejection of subsequently implanted L1210R-based tumours, but not of the L1210S ones. Notably, L1210R tumours display a twofold reduction in vivo proliferative capacity and are less aggressive in terms of mouse survival than their sensitive counterparts. Also, analysis of surface expression of molecules involved in antigen presentation and cytokine activity revealed a slight increase in IFN-γ receptor expression, a decrease of Fas molecule, and a fourfold up-regulation of MHC class I molecules in L1210R cells. Nonetheless, both cell lines were able to induce a cytotoxic response in syngeneic mice and were equally susceptible to cytotoxicity by splenic cells. Together, these findings indicate that acquisition of drug resistance by L1210 cells is accompanied by pleiotropic changes that result in reduced tumour proliferative capacity and tumorigenicity in syngeneic mice. Hence, immunological studies of MDR tumours may assist in the design of specific therapeutic strategies that complement current chemotherapy treatments.
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Acknowledgements
We thank Dr Manuel Sánchez and Dr Rosa Planells-Cases for critical reading of this manuscript, Dr Miguel Saceda and Dr Gonzalo Rubio for helpful suggestions and discussions, and Dr Agustín Beltrán de Heredia-Rueda and Dr José A. Pérez de Gracia for helpful assistance with γ-irradiation of cells and in the animal facilities.This work has been supported by the Comisión Interministerial de Ciencia y Tecnología (CICYT) and the European Commission, grants SAF-2000-0142 and 1FD97-0662-C02-01, and the Instituto de Salud Carlos III grant FISSS-01/0038-02 and 01/0038-01 (to J.A.F. and A.F-M.). Elena Martín-Orozco was the recipient of a contract from the Spanish Ministry of Science and Technology.
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Martín-Orozco, E., Ferragut, J.A., Garcia-Peñarrubia, P. et al. Acquisition of multidrug resistance by L1210 leukemia cells decreases their tumorigenicity and enhances their susceptibility to the host immune response. Cancer Immunol Immunother 54, 328–336 (2005). https://doi.org/10.1007/s00262-004-0588-7
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DOI: https://doi.org/10.1007/s00262-004-0588-7