Cetuximab and IL-15 Promote NK and Dendritic Cell Activation In Vitro in Triple Negative Breast Cancer.

Estrella Mariel Levy,José Mordoh,Estefanía Paula Juliá

doi:10.3390/cells9071573

Estrella Mariel Levy, José Mordoh + Show 1 more

Open Access

https://doi.org/10.3390/cells9071573

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Journal: Cells	Publication Date: Jun 28, 2020
Citations: 15	License type: CC BY 4.0

Affiliation: Fundación Instituto Leloir, Instituto Alexander Fleming

Abstract

Triple Negative Breast Cancer (TNBC) treatment is still challenging, and immunotherapy is a potential approach in this tumor subtype. Cetuximab is an IgG1 monoclonal antibody (mAb) directed against Epidermic Growth Factor Receptor (EGFR), a protein overexpressed in a subgroup of TNBC patients and associated with poor prognosis. Previously, we demonstrated in vitro that Cetuximab triggers Ab-dependent cell cytotoxicity against TNBC cells. In this study, using co-cultures including TNBC cells, and NK and Dendritic Cells (DCs) from healthy donors, we studied the effect of Cetuximab-activated NK cells on DC function. Given that we already demonstrated that TNBC has an immunosuppressive effect on NK cells, we also tested Cetuximab combination with IL-15. We determined that Cetuximab opsonization of TNBC cells increased IFN-γ and TNF-α production by NK cells co-cultured with DCs. Moreover, we showed that NK cells activated by TNBC cells opsonized with Cetuximab promoted tumor material uptake and maturation of DCs, as well as their ability to produce IL-12. Furthermore, the stimulation with IL-15 increased the activation of NK cells and the maturation of DCs. These results suggest that IL-15 may enhance the efficacy of Cetuximab in the treatment of TNBC by promoting activation of both NK cells and DCs.

Highlights

Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer (BC) associated with poor outcomes that lack the expression of hormone receptors and ERBB2 [1]
We show that NK cells activated by TNBC cells opsonized with Cetuximab promoted tumor material uptake and maturation of dendritic cells (DCs), as well as their ability to produce IL-12
We demonstrated that a high amount of antigen material is released from TNBC cells as a result of Cetuximab-mediated Ab-dependent cell cytotoxicity (ADCC) [17]

Summary

Introduction

Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer (BC) associated with poor outcomes that lack the expression of hormone receptors and ERBB2 [1]. TIL count is associated with improved survival, reduced recurrence risk, and augmented probability of response to neoadjuvant chemotherapy in early-stage TNBC [4]. These and other characteristics make TNBC patients proper candidates for immunotherapy [5]. NK cells recognize cells with MHC-I downmodulation, a common mechanism by which cancer cells avoid T cell recognition [8] Besides their killing capacity, NK cells are recognized as major producers of IFN-γ in many physiological and pathological conditions. NK cells are recognized as major producers of IFN-γ in many physiological and pathological conditions They produce an array of other cytokines, both proinflammatory and immunosuppressive, and growth factors. Proinflammatory cytokines from activated NK cells provide dendritic cells (DCs) signals

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