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 August 15, 2011
Citation Information: J Clin Invest. 2011;121(9):3609-3622. https://doi.org/10.1172/JCI45816.
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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 2

p-NK cell functions are altered in invasive BC patients.

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p-NK cell functions are altered in invasive BC patients. p-NK cells isol...
p-NK cells isolated from the different groups of patients were exposed to K562 cells in a direct cytotoxic assay. (A) Effective killing of K562 cells. (B) Percentage of NK cells positive for CD107. (C) Percentage of NK cells positive for IFN-γ. (D) Percentage of NK cells positive for TNF-α. (E) The multipotentiality of p-NK cells was determined from the number of functions (degranulation as measured by CD107 expression, production of IFN-γ and/or TNF-α) that each p-NK cell was able to simultaneously accomplish against K562 target cells. The E/T ratio was 1:1 in cytotoxic experiments performed against K562 cells. (F) ADCC efficiency was measured against the SK-BR-3 BC cell line preincubated without or with increasing therapeutic doses (D1 to D7) of trastuzumab. Activation of NK cells was measured by the expression of CD107. The E/T ratio was 2:1. The numbers of included patients per group were the following: B (n = 10), Tis (n = 7), LOC (n = 16), LA (n = 16), M (n = 12, except for ADCC experiments where we did not obtain enough cells to perform the test). The statistical differences between groups were established using nonparametric Mann-Whitney U test. *P < 0.05; **P ≤ 0.005. Data are represented as mean ± SEM.