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Low-dose cyclophosphamide modulates galectin-1 expression and function in an experimental rat lymphoma model

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Abstract

In recent years, one of the most important insights into tumor immunity was provided by the identification of negative regulatory pathways and immune escape strategies that greatly influence the magnitude of antitumor responses. Galectin-1 (Gal-1), a member of a family of highly conserved β-galactoside-binding proteins, has been recently shown to contribute to tumor cell evasion of immune responses by modulating survival and differentiation of effector T cells. However, there is still scarce information about the regulation of Gal-1 expression and function in vivo. Here we show that administration of a single low-dose cyclophosphamide (Cy), which is capable of restraining metastasis in the rat lymphoma model L-TACB, can also influence Gal-1 expression in primary tumor, metastasis, and spleen cells and modulate the effects of this protein on T cell survival. A time-course study revealed a positive correlation between Gal-1 expression and tumor volume in primary tumor cells. Conversely, Gal-1 expression was significantly reduced in spleen cells and lymph node metastasis throughout the period studied. Interestingly, cyclophosphamide treatment was capable of restoring the basal levels of Gal-1 expression in primary tumors and spleens. In addition, this antimetastatic agent rendered spleen T cells from tumor-bearing animals resistant to Gal-1-induced cell death. Our results suggest that, in addition to other well-known functions of cyclophosphamide, this immunomodulatory agent may also modulate Gal-1 expression and function during tumor growth and metastasis with critical implications for tumor-immune escape and immunotherapy.

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Acknowledgements

We thank J. Hirabayashi and K.I. Kasai for providing the plasmid pET21a/hGal1, Dr. E. Roggero for his advice in the immunohistochemical pictures, and Ana Rossa for her technical assistance. This research was supported by a grant from the National University of Rosario (to O.G.S), grants from the National Agency for Promotion of Science and Technology (PICT 2003-05-13787 to G.A.R.), Sales Foundation (to G.A.R.), University of Buenos Aires (M091 to G.A.R.). G.A.R. is a member of the Scientific Career of CONICET. O.G.S. is a member of the Scientific Career of C.I.U.N.R.

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Authors and Affiliations

  1. Institute of Experimental Genetics, School of Medical Sciences, National University of Rosario, Santa Fe 3100, 2000, Rosario, Argentina

    Mariano F. Zacarías Fluck, María J. Rico, Silvia I. Gervasoni & O. Graciela Scharovsky

  2. Division of Immunogenetics, Hospital de Clínicas “José de San Martín”, University of Buenos Aires, Buenos Aires, Argentina

    Juan M. Ilarregui, Marta A. Toscano & Gabriel A. Rabinovich

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  1. Mariano F. Zacarías Fluck
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  2. María J. Rico
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  3. Silvia I. Gervasoni
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  4. Juan M. Ilarregui
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  5. Marta A. Toscano
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  6. Gabriel A. Rabinovich
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  7. O. Graciela Scharovsky
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Correspondence to O. Graciela Scharovsky.

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Mariano F. Zacarías Fluck and María J. Rico contributed equally to this work.

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Zacarías Fluck, M.F., Rico, M.J., Gervasoni, S.I. et al. Low-dose cyclophosphamide modulates galectin-1 expression and function in an experimental rat lymphoma model. Cancer Immunol Immunother 56, 237–248 (2007). https://doi.org/10.1007/s00262-006-0176-0

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