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NXS2 murine neuroblastomas express increased levels of MHC class I antigens upon recurrence following NK-dependent immunotherapy

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Abstract

We evaluated recurrent NXS2 neuroblastoma tumors that developed following NK- or T-cell–mediated immunotherapy in tumor-bearing mice. Recurrent tumors developed following an NK-dependent antitumor response using a suboptimal dose of hu14.18-IL2, a humanized IL-2 immunocytokine targeted to the GD2-ganglioside. This treatment initially induced complete resolution of measurable tumor in the majority of mice, followed, however, by delayed tumor recurrence in some mice. These recurrent NXS2 tumors revealed markedly enhanced (> fivefold) MHC class I antigen expression when compared with NXS2 tumors growing in PBS-treated control mice. A similar level of enhanced MHC class I antigen-expression could be induced on NXS2 cells in vitro by culturing with interferon γ, and was associated with reduced susceptibility to both NK-cell–mediated tumor cell lysis and antibody-dependent cellular cytotoxicity in vitro. In contrast, Flt3-ligand treatment of NXS2-bearing mice induced a protective T-cell–dependent antitumor memory response. Recurrent NXS2 tumors that developed following Flt3-L therapy revealed a decreased expression of MHC class I antigens. While NXS2 tumors are susceptible to in vivo destruction following either hu14.18-IL2 or Flt3-ligand immunotherapies, these results suggest that some tumor cells may be selected to survive and progress by expressing either higher or lower levels of MHC class I antigen in order to resist either NK- or T-cell–mediated antitumor responses, respectively.

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Abbreviations

ADCC:

antibody-dependent cellular cytotoxicity

Flt3-L:

Flt3-ligand

GD2 :

GD2-disialoganglioside

IC:

immunocytokine

mAb:

monoclonal antibody

NB:

neuroblastoma

NXS2:

transplantable murine neuroblastoma

s.c.:

subcutaneous

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Acknowledgements

The authors wish to thank Drs Nancy Scherer, Stewart Lyman, and Michael Widmer of Immunex (Seattle, WA) for provision of Flt3-L and sharing of data; Kathy Schell for assistance with flow cytometric analyses; and Drs Jacek Gan and Mark Albertini of UW-Madison, and Oscar Kashala of EMD (Durham, NC) for helpful discussions. This work was supported by NIH Grants CA32685 and CA14520, Army Grant DAMD BC990300, and a grant from the Midwest Athletes for Childhood Cancer Fund. This study is dedicated to the memory of Lewie Clay Neal.

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Authors and Affiliations

  1. University of Wisconsin Comprehensive Cancer Center, University of Wisconsin-Madison, 600 Highland Ave., K4/448, Madison, WI 53792, USA

    Zane C. Neal, Michael Imboden, Alexander L. Rakhmilevich, Kyung-Mann Kim, Jacquelyn A. Hank, Jean Surfus, John R. Dixon & Paul M. Sondel

  2. Department of Immunology, Scripps Research Institute, La Jolla, CA 92037, USA

    Holger N. Lode & Ralph A. Reisfeld

  3. EMD-Lexigen Research Centers, Billerica, MA 01821, USA

    Stephen D. Gillies

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  1. Zane C. Neal
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  2. Michael Imboden
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Correspondence to Paul M. Sondel.

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Neal, Z.C., Imboden, M., Rakhmilevich, A.L. et al. NXS2 murine neuroblastomas express increased levels of MHC class I antigens upon recurrence following NK-dependent immunotherapy. Cancer Immunol Immunother 53, 41–52 (2004). https://doi.org/10.1007/s00262-003-0435-2

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