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  • Open Access

Modulation of tumour directed B cell responses by NK cells

  • M Jensen1, 2Email author,
  • A Buhl1, 2,
  • C Hoyer1, 2,
  • S Schmitz1, 2,
  • S Tawadros2,
  • H Harald-Sedlacek3,
  • J Schultze2 and
  • F Berthold1
Cancer Cell International20044(Suppl 1):S28

https://doi.org/10.1186/1475-2867-4-S1-S28

Received: 28 April 2004

Published: 1 July 2004

Keywords

Small Cell Lung Cancer CellCell Lung Cancer Cell LineSingle Subcutaneous InjectionIgG2a IsotypeTumour Specific Antibody

Background and aim

Spontaneous natural killer cell (NK cell) activity against malignant cells is important for development of tumour directed Th1 biased and cytotoxic T cell (CTL) responses (Kelly et al., Nature 2002; Geldhof et al, Blood 2002) resulting in protection from tumour growth in mouse models. Aim of our investigations was to study the significance of NK cell activity on tumour directed B cell immunity.

Material and methods

Tumour directed B-cell responses were studied in C57Bl/6 mice, NK cells depleted in the experimental group by i.v. injection of anti-ASGM1 antibodies. Mice were immunized human IMR5-75 neuroblastoma cells and tumour specific antibody responses measured by flow cytometry and GD2 specific ELISA.

Results

Spontaneous murine NK activity against the IMR5-75 tumor model as a requested condition for analysing NK cells impact on adaptive responses were demonstrated in SCID mice lacking T- and B-cells, but having functional intact NK cells. Single subcutaneous injections of 3.45–4.0 × 107 IMR5-75 cells induced growth of tumor nodules in only 3/10 mice, but in 10/10 NK depleted mice (P < 0.000), demonstrating spontaneous murine NK activity against IMR5-75 cells. 4/4 C57Bl/6 mice immunized with irradiated IMR5-75 cells for two weeks developed significant global serum IgG responses (titer: 2 × 1:160, 2 × 1:320) against the immunizing cells (flow cytometry), while NK depleted control animals revealed only poor responsiveness (titer < 1:40; P = 0.003). Interestingly IgG responses in NK depleted mice after three weeks of immunisation were similar to the controls., This may reflect a delayed B cell answer in NK depleted mice. Dissection of IgG1 and IgG2a isotype specific responses demonstrated a strong impairment in Th1 biased IgG2a track and surprisingly in contrast a "compensatory" enforced Th2 oriented IgG1 response. ELISA based antibody measurement against the tumor specific GD2 ganglioside confirmed the flow cytometry data and demonstrated anti-GD2 responses only in NK depleted animals and only from the Th2 oriented IgG1 isotype. Dissection of GD2 specific IgG1 and IgG2a responses in 8 F004/C57 hybrid mice immunised with the GD2 expressing small cell lung cancer cell line H69 confirmed the Th2 biased GD2 specific B cell response in NK depleted mice as an independent control experiment.

Conclusions

Our data demonstrate an important NK cell regulatory function on the development of tumour directed B cell responses. Since Th1 biased IgG production results in antibodies with higher affinity (IgG1 and IgG3 in humans) for Fc-gamma-receptors than Th2 responses impairment of tumor directed ADCC will be a consequence. Tumour vaccination strategies will have to pay attention on the NK cell status of patients e.g. after chemo- or radiotherapy.

Authors’ Affiliations

(1)
Department of Pediatric Oncology and -Haematology, University of Cologne, Cologne, Germany
(2)
Molecular Tumor Biology and Tumor Immunology, University of Cologne, Germany
(3)
MedInnova GmbH, Marburg, Germany

Copyright

© Author(s); licensee BioMed Central Ltd. 2004

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