Natural killer activity of peripheral-blood mononuclear cells in breast cancer patients

Dewan, Zahidunnabi; Takada, Masahiro; Takahashi, Hiroshi; Deng, Xuewen; Ahmed, Sunjida; Yamamoto, Naoki; Toi, Masakazu

doi:10.1016/j.biopha.2009.02.003

Cited by 42 publications

(36 citation statements)

References 19 publications

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“…Accordingly, antitumor immunity is frequently deficient in patients with solid tumors (28, 29). We have confirmed here that p-NK cell activity, notably IFN-γ pro- duction, is strongly impaired in invasive breast tumors (39,40), especially when the stage of disease is advanced. In situ, the immune infiltrate has long been neglected, but we now know that it is not the quantity but the quality of the immune infiltrate, mostly composed of cytotoxic cells, that can predict tumor outcome of several cancers, such as early-stage colorectal cancer, gastrointestinal tumor, pulmonary adenocarcinoma, and, more recently, BC (41)(42)(43).…”

Section: Discussionsupporting

confidence: 81%

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

Mamessier¹,

Sylvain²,

Thibult³

et al. 2011

J. Clin. Invest.

539

494

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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. IntroductionBreast cancer (BC) is the primary cause of cancer deaths in women. The main cause of this mortality is the metastatic spread to other organs (1). Metastasis occurs when tumor cells acquire invasive features (2) and the ability to escape from antitumor immunity (3, 4). Defects in antitumor immunity may also facilitate BC occurrence. Indeed, mice deficient in IFN-γ production spontaneously develop mammary tumors (5). Breast tumor cells transplanted into NOD/SCID mice (which lack adaptive immunity) form noninvasive tumors, whereas the same cells transplanted into NOD/SCID/γ-c null mice (no adaptive immunity and no NK cells) form invasive tumors that metastasize rapidly (6). This effect is strictly dependent on NK cells (7). Similarly, in a highly metastatic model, BC metastasized to the lung only after elimination of NK cells by Tregs (8).Advanced BC patients show defects in antitumor immunity, such as alterations of DC maturation (9) and an increase in Treg infiltrates (10). Major impairment of peripheral blood NK cell maturation and cytotoxic functions has also been reported in metastatic BC (11). Several gene expression profiling studies have shown that a better outcome is associated with a strong cytotoxic infiltrate containing NK cells (12)(13)(14)(15). These data suggest that BC progression is linked to antitumor immunity efficiency and particularly to NK cells. However, the precise relationships between NK cells and BC progression in humans have not been studied so far.

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Section: Discussionsupporting

confidence: 81%

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

Mamessier¹,

Sylvain²,

Thibult³

et al. 2011

J. Clin. Invest.

539

494

View full text Add to dashboard Cite

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“…Patients induced to complete or partial remission by TTZ alone were found to have higher ADCC and higher infiltration of cytotoxic lymphocytes in situ (13). However, NK cell activities of PBMCs from breast cancer patients are significantly lower compared with those of healthy individuals (53), and there is a great heterogeneity of NK cell-ADCC activity among breast cancer patients. Moreover, assessment of ADCC in metastatic breast cancer patients treated with a combination of TTZ and IL-2 or with IL-12 alone failed to find that ADCC correlates with clinical responses (54,55).…”

Section: Discussionmentioning

confidence: 98%

Stimulated γδ T Cells Increase the In Vivo Efficacy of Trastuzumab in HER-2+ Breast Cancer

Capietto

Martinet

Fournié

2011

The Journal of Immunology

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One fourth of women with HER-2+ metastatic breast carcinoma are treated with a combination regimen with trastuzumab, but the frequent resistance to this Ab requires definition of new means to improve its bioactivity. The mechanisms of action of trastuzumab involve several pathways including Ab-dependent cellular cytotoxicity. Because human γδ T lymphocytes mediate Ab-dependent cellular cytotoxicity and can be activated further by phosphoantigens, these cells are prone to improve the efficacy of Abs, as recently demonstrated for CD20+ B cell lymphomas. Whether this concept applies as well with carcinomas remained to be demonstrated in vivo, however. In this study, we asked whether a combination of trastuzumab and phosphoantigen-stimulated γδ lymphocytes increases the efficacy of trastuzumab against HER-2+ breast carcinoma cell lines in vivo. We report that repeated infusions of this combination had a better efficacy than that of trastuzumab alone against HER-2+ mammary carcinoma xenografts in mice. In these models, reduction of tumor growth was observed together with trastuzumab opsonization of HER-2+ cells and tumor infiltration by γδ lymphocytes. In addition in humans, the mammary carcinomas of 27 of 30 patients showed significant γδ T cell infiltrates. Altogether, these findings indicate that combination of trastuzumab and stimulated γδ cells represents a new strategy to improve the efficacy of Herceptin (trastuzumab) in HER-2+ breast cancer.

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“…However, to date, nothing is known about the different susceptibility to antitumor immunity of the different breast cancer subtypes, as well as about the mechanisms involved. Among the actors of antitumor immunity, natural killer (NK) cells are the immune cells specialized in host defense against transformed cells (7,8). This is due to an innate ability to distinguish normal from "modified" cancer cells (9).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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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.

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Natural killer activity of peripheral-blood mononuclear cells in breast cancer patients

Cited by 42 publications

References 19 publications

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

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

Stimulated γδ T Cells Increase the In Vivo Efficacy of Trastuzumab in HER-2+ Breast Cancer

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

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