Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity
Emilie Mamessier, … , Alessandro Moretta, Daniel Olive
Emilie Mamessier, … , Alessandro Moretta, Daniel Olive
Published September 1, 2011; First published August 15, 2011
Citation Information: J Clin Invest. 2011;121(9):3609-3622. https://doi.org/10.1172/JCI45816.
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Categories: Research Article Oncology

Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity

Abstract

NK cells are a major component of the antitumor immune response and are involved in controlling tumor progression and metastases in animal models. Here, we show that dysfunction of these cells accompanies human breast tumor progression. We characterized human peripheral blood NK (p-NK) cells and malignant mammary tumor-infiltrating NK (Ti-NK) cells from patients with noninvasive and invasive breast cancers. NK cells isolated from the peripheral blood of healthy donors and normal breast tissue were used as controls. With disease progression, we found that expression of activating NK cell receptors (such as NKp30, NKG2D, DNAM-1, and CD16) decreased while expression of inhibitory receptors (such as NKG2A) increased and that this correlated with decreased NK cell function, most notably cytotoxicity. Importantly, Ti-NK cells had more pronounced impairment of their cytotoxic potential than p-NK cells. We also identified several stroma-derived factors, including TGF-β1, involved in tumor-induced reduction of normal NK cell function. Our data therefore show that breast tumor progression involves NK cell dysfunction and that breast tumors model their environment to evade NK cell antitumor immunity. This highlights the importance of developing future therapies able to restore NK cell cytotoxicity to limit/prevent tumor escape from antitumor immunity.

Authors

Emilie Mamessier, Aude Sylvain, Marie-Laure Thibult, Gilles Houvenaeghel, Jocelyne Jacquemier, Rémy Castellano, Anthony Gonçalves, Pascale André, François Romagné, Gilles Thibault, Patrice Viens, Daniel Birnbaum, François Bertucci, Alessandro Moretta, Daniel Olive

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Figure 7

Impact of breast tumor stroma on p-NK cells.

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Impact of breast tumor stroma on p-NK cells. (A) p-NK cells were culture...
(A) p-NK cells were cultured for 48 hours in complete medium, dissociation supernatant from tumor-free samples (H, n = 4), or dissociation supernatant from malignant samples (T, n = 12). The main NK cell receptors were then phenotyped. The resulting expressions were submitted to TMEV. The significance of the observed variation was measured with a Kruskal-Wallis (KW) test. (B) Alterations of NK cell functions were measured from 10 different tumor supernatants. CD69 expression, CD107 degranulation, IFN-γ, and TNF-α synthesis and percentage of absolute dead K562 cells were measured from p-NK cells cultured in complete medium (white bars) and p-NK cells exposed to tumor supernatant (gray bars). (C) The correlation matrix of the R coefficients was obtained with a Spearman’s test between the quantitative levels of tissue-associated soluble factors and paired NK cell receptors expression. (D) Correlation between TGF-β1 levels found in breast tumor supernatants and the respective NPI. (E) Partial restoration of NK cell functions after preincubation of tumor supernatants (n = 10) with blocking TGF-β1 antagonist antibody. Variations were evaluated with a nonparametric Mann-Whitney U test. *P < 0.05; **P ≤ 0.005; ***P ≤ 0.0005. Data are represented as mean ± SEM.