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Anti-LFA-1 antibodies enhance metastasis of ocular lymphoma to the brain and contralateral eye

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Abstract

Previously we demonstrated that intraperitoneal (IP) inoculation of Rev-2-T-6 mouse lymphoma into syngeneic Balb/c hosts resulted in brain metastasis, migration along the optic nerve sheath, and ocular infiltration. In a second model: intravitreal inoculation of Rev-2-T-6 cells, the developing lymphoma was largely confined within the eye, seldom breaching the retinal pigment epithelium to reside in the choroid and sclera. There was no retrograde infiltration into the brain. Here, we describe a third, complementary model, whereby intravitreal inoculation of Rev-2-T-6 cells into Balb/c mice, followed by repeated IP inoculations of anti-LFA-1/CD11a monoclonal antibodies, results in extensive infiltration of the choroid, sclera, conjunctiva, eyelids and orbit. Furthermore, the lymphoma cells metastasize along the optic nerve sheath into the brain, and through the contralateral optic nerve tract into the contralateral eye. There is no systemic involvement of the lymphoma. Furthermore, anti-LFA-1 treatment results in elevated levels of serum anti-Rev-2-T-6 antibodies. Inoculation of Rev-2-T-6 cells into the vitreous of severe combined immune deficient mice demonstrates a course of clinical signs and histopathological findings similar to those in immune-competent mice treated with anti-LFA-1 antibodies, including invasion of the contralateral eye. Taken together, these findings suggest that confinement of Rev-2-T-6 lymphoma cells to the eye depends on active immune surveillance using a population of effector cells expressing the cell surface integrin LFA-1. Impairing this protection enhances tumor aggressiveness within the eye, and the likelihood of early retrograde lymphoma metastasis into the brain and the contralateral eye.

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Abbreviations

ICAM-1:

Intracellular adhesion molecule-1

LFA-1:

Lymphocyte function-associated antigen-1

SCID:

Severe combined immune deficient

IP:

Intraperitoneal

APCs:

Antigen presenting cells

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Acknowledgments

This work was supported by the A.M.N foundation, Jerusalem (JH) and by the Intramural Research Programs of the National Institutes of Health, National Eye Institute (DS, CCC) and National Cancer Institute (JH, MMG).

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Authors and Affiliations

  1. Department of Cell and Developmental Biology, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel

    Jacob Hochman

  2. Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892-1857, USA

    DeFen Shen & Chi-Chao Chan

  3. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Michael M. Gottesman

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  1. Jacob Hochman
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  2. DeFen Shen
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  3. Michael M. Gottesman
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  4. Chi-Chao Chan
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Correspondence to Jacob Hochman or Chi-Chao Chan.

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Hochman, J., Shen, D., Gottesman, M.M. et al. Anti-LFA-1 antibodies enhance metastasis of ocular lymphoma to the brain and contralateral eye. Clin Exp Metastasis 30, 91–102 (2013). https://doi.org/10.1007/s10585-012-9512-2

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  • DOI: https://doi.org/10.1007/s10585-012-9512-2

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