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IL-2- or IL-15-activated NK cells enhance Cetuximab-mediated activity against triple-negative breast cancer in xenografts and in breast cancer patients

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Abstract

Triple-negative breast cancer (TNBC) patients do not benefit from target-specific treatments and is associated with a high relapse rate. Epidermal growth factor receptor is frequently expressed in TNBC and is a candidate for new therapies. In this work, we studied Cetuximab-mediated immune activity by NK cells. Thirteen activating/inhibitory receptors were examined on peripheral blood and tumor infiltrating NK cells. NK-cell functionality was evaluated using as effectors tumor-modulated NK cells and NK cells from patients. We evaluated the treatment with Cetuximab plus IL-2 or IL-15 in vivo in TNBC xenografts. Tumor NK-cells receptor profile showed upregulation of inhibitory receptors and downregulation of activating ones. Tumor-modulated NK cells were less cytotoxic. They could perform antibody-dependent cellular cytotoxicity (ADCC) triggered by Cetuximab, although impaired, it could still be restored by stimulation with IL-2 or IL-15. Patients with advanced disease displayed diminished levels of ADCC compared to healthy volunteers. ADCC was restored and potentiated with both cytokines, which were also effective in enhancing the therapeutic activity of Cetuximab in vivo. The combination of Cetuximab with IL-15 and IL-2 may be considered an attractive therapeutic approach to enhance the clinical efficacy of Cetuximab in TNBC.

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Abbreviations

ADCC:

Antibody-dependent cellular cytotoxicity

BC:

Breast cancer

EGFR:

Epidermal growth factor receptor

HD:

Healthy donors

IHC:

Immunohistochemistry

IS:

In situ breast cancer patients

Inv:

Invasive breast cancer patients

LA:

Locally advanced breast cancer patients

PBNK:

Peripheral blood NK cells

TNBC:

Triple-negative breast cancer

TINK:

Tumor infiltrating NK cells

SINK:

Stroma infiltrating NK cells

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Acknowledgments

This study was supported by Grants from Fundación Sales, Fundación P. Mosoteguy, Fundación Cáncer (FUCA), Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT) and Fundación María Calderón de la Barca. We are grateful to Ms. María Luisa Poljak for bibliographic support and Ms. Paula Blanco for technical assistance. We also thank the Servicio de Cirugía, Servicio de Patología and Servicio de Hemoterapia del Instituto Alexander Fleming.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Centro de Investigaciones Oncológicas – Fundación Cáncer FUCA, Buenos Aires, Argentina

    María P. Roberti, Yamila S. Rocca, María B. Pampena, Juan M. Arriaga, Michele Bianchini, María M. Barrio, José Mordoh & Estrella M. Levy

  2. Instituto Alexander Fleming, Buenos Aires, Argentina

    Mora Amat, José Loza, Federico Coló, Verónica Fabiano, Carlos M. Loza, Enzo Domenichini, Reinaldo Chacón & José Mordoh

  3. Hospital Interzonal General de Agudos Eva Perón, San Martín, Argentina

    Alicia I. Bravo

  4. Fundación Instituto Leloir, IIBBA-CONICET, Buenos Aires, Argentina

    José Mordoh

  5. Zabala 2836, Buenos Aires, 1426, Argentina

    Estrella M. Levy

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  1. María P. Roberti
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  2. Yamila S. Rocca
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Corresponding author

Correspondence to Estrella M. Levy.

Electronic supplementary material

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10549_2012_2287_MOESM1_ESM.tif

Supplementary material 1 Supplementary Fig. 1. NK cell receptor expression in BC patients. Percentage of each receptor shown was calculated on CD45+CD3-CD56+ population in PBNK (black circles), SINK (black triangles) and TINK (white squares). Means are depicted as horizontal bars. *: P<0.05; **: P<0.01; ***: P<0.001. (TIFF 5768 kb)

10549_2012_2287_MOESM2_ESM.tif

Supplementary material 2 Supplementary Fig. 2. Proliferation assay in co-cultured NK cells. Purified NK cells were stained with 10 μM CFSE. After 5 days of co-culture with tumor cells, MFI of CFSE was measured on NK cell population by flow cytometry. (TIFF 651 kb)

10549_2012_2287_MOESM3_ESM.tif

Supplementary material 3 Supplementary Fig. 3. HLA-I expression in TNBC cell lines. HLA-I expression was measured by flow cytometry. IIB-BR-G and IIB-BR-G MT cell lines were incubated with anti-HLA ABC antibody (dark empty peaks) or control isotype (gray fill peaks). (TIFF 546 kb)

Supplementary material 4 (TIFF 1839 kb)

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Roberti, M.P., Rocca, Y.S., Amat, M. et al. IL-2- or IL-15-activated NK cells enhance Cetuximab-mediated activity against triple-negative breast cancer in xenografts and in breast cancer patients. Breast Cancer Res Treat 136, 659–671 (2012). https://doi.org/10.1007/s10549-012-2287-y

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