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Transient activation of tumor-associated T-effector/memory cells promotes tumor eradication via NK-cell recruitment: minimal role for long-term T-cell immunity in cure of metastatic disease

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Abstract

Local delivery of IL-12 and GM-CSF to advanced primary tumors results in T- and NK-cell-dependent cure of disseminated disease in a murine spontaneous lung metastasis model. Post-therapy functional dynamics of cytotoxic T- and NK-cells were analyzed in primary and metastatic tumors to determine the specific roles of each subset in tumor eradication. Time-dependent depletion of CD8+ T and NK-cells demonstrated that CD8+ T-cells were critical to eradication of metastatic tumors within 3 days of treatment, but not later. In contrast, NK-cells were found to be essential to tumor regression for at least 10 days after cytokine delivery. Analysis of tumor-infiltrating lymphocyte populations in post-therapy primary tumors demonstrated that treatment resulted in the activation of tumor-associated CD8+ T-cells within 24 h as determined by IFNγ and perforin production. T-cell activity peaked between days 1 and 3 and subsided rapidly thereafter. Activation was not accompanied with an increase in cell numbers suggesting that treatment mobilized pre-existing T-effector/memory cells without inducing proliferation. In contrast, therapy resulted in a ≥3-fold enhancement of both the quantity and the cytotoxic activity of NK-cells in primary and metastatic tumors on day 3 post-therapy. NK-cell activity was also transient and subsided to pre-therapy levels by day 5. Depletion of CD4+ and CD8+ T-cells prior to treatment completely abrogated NK-cell infiltration into primary and metastatic tumors demonstrating the strict dependence of NK-cell recruitment on pre-existing T-effector/memory cells. Treatment failed to induce significant NK-cell infiltration in IFNγ-knockout mice establishing the central role of IFNγ in NK-cell chemotaxis to tumors. These data show that transient activation of tumor-associated T-effector/memory and NK-cells, but not long-term CD8+ T-cell responses, are critical to suppression of metastatic disease in this model; and reveal a novel role for pre-existing adaptive T-cell immunity in the recruitment of innate effectors to tumors.

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Acknowledgments

The authors thank Dr. Stan Wolf of Wyeth Pharmaceuticals for providing the recombinant IL-12 and for his continued support of our studies.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, 138 Farber Hall, 3435 Main Street, Suny, Buffalo, NY, 14214, USA

    Tao Gu, Mehmet O. Kilinc & Nejat K. Egilmez

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  1. Tao Gu
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  2. Mehmet O. Kilinc
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  3. Nejat K. Egilmez
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Correspondence to Nejat K. Egilmez.

Additional information

This work was supported by NIH/NCI grant R01-CA100656-01A1 to N.K.E.

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Gu, T., Kilinc, M.O. & Egilmez, N.K. Transient activation of tumor-associated T-effector/memory cells promotes tumor eradication via NK-cell recruitment: minimal role for long-term T-cell immunity in cure of metastatic disease. Cancer Immunol Immunother 57, 997–1005 (2008). https://doi.org/10.1007/s00262-007-0430-0

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  • DOI: https://doi.org/10.1007/s00262-007-0430-0

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