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Characterizing the anti-tumor function of adoptively transferred NK cells in vivo

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Abstract

Natural killer (NK) cells represent a promising cell type to utilize for effective adoptive immunotherapy. However, little is known about the important cytolytic molecules and signaling pathways used by NK cells in the adoptive transfer setting. To address this issue, we developed a novel mouse model to investigate the trafficking and mechanism of action of these cells. We demonstrate that methylcholanthrene-induced RKIK sarcoma cells were susceptible to NK cell-mediated lysis in vitro and in vivo following adoptive transfer of NK cells in C57BL/6 RAG-2−/−γc−/− mice. Cytotoxic molecules perforin, granzymes B and M as well as the death ligand TRAIL and pro-inflammatory cytokine IFN-γ were found to be important in the anti-tumor effect mediated by adoptively transferred NK cells. Importantly, we demonstrate that adoptively transferred NK cells could traffic to the tumor site and persisted in vivo which correlated with the anti-tumor effect observed. Overall, the results of this study have important implications for enhancing NK cell-based immunotherapies.

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Acknowledgments

We would like to acknowledge the assistance of the Peter MacCallum Cancer Centre Experimental Animal Facility technicians for animal care, in particular Michelle Stirling and Leanne McNiff for maintenance of the gene-targeted mice used in this study. We would also like to acknowledge Nicole McLaughlin for generating some of the antibodies used in these experiments. This work was funded by project grants from the National Health and Medical Research Council (NHMRC), Cancer Council of Victoria and the Susan Komen Breast Cancer Foundation. M.H. Kershaw and P.K. Darcy were supported by a NHMRC Senior Research Fellowship and Career Development Award, respectively. M.J. Smyth was supported by a NHMRC Senior Principal Research Fellowship. N.M. Haynes was supported by a NHMRC CJ Martin Fellowship.

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Authors and Affiliations

  1. Cancer Immunology Program, Cancer Immunotherapy Research Laboratory, Peter MacCallum Cancer Centre, 14 St Andrews Place, East Melbourne, VIC, 3002, Australia

    Hollie J. Pegram, Nicole M. Haynes, Mark J. Smyth, Michael H. Kershaw & Phillip K. Darcy

  2. Department of Pathology, University of Melbourne, Melbourne, Australia

    Mark J. Smyth, Michael H. Kershaw & Phillip K. Darcy

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  1. Hollie J. Pegram
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  2. Nicole M. Haynes
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  3. Mark J. Smyth
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  4. Michael H. Kershaw
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  5. Phillip K. Darcy
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Correspondence to Phillip K. Darcy.

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M. H. Kershaw and P. K. Darcy contributed equally as senior authors.

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Pegram, H.J., Haynes, N.M., Smyth, M.J. et al. Characterizing the anti-tumor function of adoptively transferred NK cells in vivo. Cancer Immunol Immunother 59, 1235–1246 (2010). https://doi.org/10.1007/s00262-010-0848-7

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