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.

Key Points Normal IgG and IgG2 differentially inhibit HIT antibody-dependent platelet activation according to the FcγRIIA H131R polymorphism. This variable effect of IgG and IgG2 probably explains the higher risk of thrombosis in patients homozygous for the FcγRIIA 131R allele.

Objective Rituximab, a monoclonal antibody specifically targeting CD20, induces B cell depletion and is effective in the treatment of rheumatoid arthritis (RA). This study was undertaken to evaluate whether routine monitoring of lymphocyte subpopulations, especially T cells, may be useful in patients receiving rituximab for RA. Methods We examined data on all RA patients receiving rituximab between July 2007 and November 2012 in our center. Peripheral blood CD3+, CD4+, CD8+, CD3−CD56+, and CD19+ lymphocyte counts before and during the first course of rituximab were measured by flow cytometry. The Mann‐Whitney nonparametric test was used to compare lymphocyte subpopulation counts before and during treatment. Results Data on 52 patients were examined. Rituximab induced unexpected and substantial depletion of T cells, mainly CD4+ cells, in most patients. The CD4+ cell count decreased by a mean ± SD of 37 ± 33% as compared to baseline at week 12, reaching <200 cells/μl in 3 patients. Importantly, lack of CD4+ cell depletion was associated with no clinical response. Therefore, the mechanism of action of rituximab may depend at least in part on T cells. Conclusion Rituximab induces substantial T cell depletion, mainly of CD4+ cells, which is associated with the clinical response in RA. Routine monitoring of T cells may be useful in the clinical setting of RA.