Human Breast Tumor Cells Induce Self-Tolerance Mechanisms to Avoid NKG2D-Mediated and DNAM-Mediated NK Cell Recognition

Emilie Mamessier,François Bertucci,Rémy Castellano,Aude Sylvain,Gilles Houvenaeghel,Alessandro Moretta,Pascal Finetti,Emmanuelle Charaffe-Jaufret,Daniel Birnbaum,Daniel Olive

doi:10.1158/0008-5472.can-11-0792

Emilie Mamessier, François Bertucci + Show 8 more

Open Access

https://doi.org/10.1158/0008-5472.can-11-0792

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Abstract

Breast cancer is the leading cause of death for women between the ages of 35 to 65. This is mostly due to intertumor heterogeneity and the lack of specific therapies for all subtypes. However, some breast cancers with an unexpected good prognosis are associated with enhanced antitumor immunity in situ. We studied whether breast cancer subtypes might have different susceptibilities to natural killer (NK) cells' antitumor immunity. We collected a large public set of microarray data for primary breast tumors and determined NK cell ligand expression. We found that despite heterogeneous levels of inhibitory HLA members, NKG2D ligands and DNAM ligands are expressed in virtually all breast tumor subtypes. Functional experiments in breast cancer subtypes expressing various levels of NK cell ligands showed that NK-mediated cytotoxicity is mainly HLA, NKG2D, and DNAM dependent. In parallel, we showed that cell lines and primary breast tumor cells secrete soluble inhibitory factors that alter NK cell functions. Finally, we showed that these mechanisms of escape occur in vivo in the MMTV-Neu model of spontaneous murine breast cancer. Our study shows that breast cancer cells, independent of the subtype, have developed different mechanisms to escape from NK cells' antitumor immunity. These results emphasize the role of NK cells in breast tumor clearance and underlie the importance of devising future therapy aiming at enhancing NK cell-mediated recognition in parallel with the prevention of the tumor-editing process.

Highlights

Breast cancer remains the leading cause of death for women of 35 to 65 years old [1]
We extracted the mRNA expression values of 15 known ligands of natural killer (NK) cell receptors from a public DNA microarray database of breast cancers, including 98 luminal A, 64 luminal B, 37 ERBB2, 43 normal-like, 110 basal tumors, and 4 healthy mammary tissues. mRNA values were mean centered on healthy tissues (Fig. 1A), allowing for a measure of relative expression of these genes in breast cancer subtypes compared with healthy mammary tissues
NK cells activation depends on cell surface receptors, which are selected during NK cells ontogeny, and results from a balance between incoming inhibitory and activating signals

Summary

Introduction

Breast cancer remains the leading cause of death for women of 35 to 65 years old [1]. Gene expression studies have shown the heterogeneity of the disease and identified at least 5 clinically relevant molecular subtypes of breast tumors: luminal A, luminal B, ERBB2, basal, and normal-like [2]. These subtypes are associated with distinct gene expression patterns and, more importantly, with different clinical outcome. Basal breast cancers are highly proliferative tumors of poor prognosis, which frequently do not express hormone receptors and ERBB2 and cannot benefit from any available targeted therapy. DNAM-1 binds the receptors PVR and PVRL2/ Nectin-2/CD112, whereas the ligand of B7-H3 is unknown The integration of these opposing signals determines whether a given NK cell will eliminate or not a potential target. These should be targeted to restore NK cells cytotoxicity against solid breast tumors

Material and Methods

Results

B Anti-HLAABC

Discussion

IV V VI VI VI No No No Yes Yes Yes

Disclosure of Potential Conflicts of Interest