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Supplementary Data 1 from Human Breast Tumor Cells Induce Self-Tolerance Mechanisms to Avoid NKG2D-Mediated and DNAM-Mediated NK Cell Recognition

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posted on 2023-03-30, 20:52 authored by Emilie Mamessier, Aude Sylvain, François Bertucci, Rémy Castellano, Pascal Finetti, Gilles Houvenaeghel, Emmanuelle Charaffe-Jaufret, Daniel Birnbaum, Alessandro Moretta, Daniel Olive

PDF file - 320K, Supplemental Data 1: Ligands and receptors respectively expressed by tumor and NK-cells. Natural killer (NK) cells are components of the innate immune system that play a central role against tumor cells. They have an innate ability to distinguish normal from "modified" cells, such as cancer cells, through a broad range of activating and inhibitory receptors. These receptors act like little sensors of the malignant self (Moretta et al, 2006); the integration of these opposite signals determines whether an NK-cell will eliminate a potential target or not. NK-cell activating receptors are the natural cytotoxicity receptors (NKp30, NKp46 and NKp44) and NKG2D. They recognize various ligands expressed by transformed cells and/or stressed or activated cells. To date, NKp30 has two described ligands, B7H6 and BAT3. NKG2D can bind MICA, MICB and the members of the ULBP family. The ligand(s) of NKp46 or NKp44 are unknown. The main NK-cell inhibitory receptors are the killer immunoglobulin receptors (KIRs) and NKG2A (Moretta et al., 1995 & 2001), which recognize members of the HLA-I family expressed by normal cells, respectively HLA-A, -B or -C for the KIRs and HLA-E for NKG2A. The signal is fine-tuned by co-activators such as DNAM-1, CD2, NKp80, 2B4, NTBA and co-inhibitors such as the CD85 family, B7-H3 or LAIR. Among co-activator receptors, DNAM-1 binds the heterodimer PVR/Nectin2 receptors, CD2 binds CD58, NTBA binds another NTBA molecule, and 2B4 binds CD48. The co-inhibitory receptors from the CD85 family bind HLA-I molecules, while ligands of the LAIR family and B7H3 are still unknown.

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ARTICLE 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. Cancer Res; 71(21); 6621–32. ©2011 AACR.

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