Foxp3+ T Cells Induce Perforin-Dependent Dendritic Cell Death in Tumor-Draining Lymph Nodes

Abstract

Regulatory T (Treg) cells limit the onset of effective antitumor immunity, through yet-ill-defined mechanisms. We showed the rejection of established ovalbumin (OVA)-expressing MCA101 tumors required both the adoptive transfer of OVA-specific CD8(+) T cell receptor transgenic T cells (OTI) and the neutralization of Foxp3(+) T cells. In tumor-draining lymph nodes, Foxp3(+) T cell neutralization induced a marked arrest in the migration of OTI T cells, increased numbers of dendritic cells (DCs), and enhanced OTI T cell priming. Using an in vitro cytotoxic assay and two-photon live microscopy after adoptive transfer of DCs, we demonstrated that Foxp3(+) T cells induced the death of DCs in tumor-draining lymph nodes, but not in the absence of tumor. DC death correlated with Foxp3(+) T cell-DC contacts, and it was tumor-antigen and perforin dependent. We conclude that Foxp3(+) T cell-dependent DC death in tumor-draining lymph nodes limits the onset of CD8(+) T cell responses.

Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4+T cells

“…The demonstration that systemic depletion of Tregs favors tumor rejection in mouse models highlighted their contribution in tumor progression (4). Whereas it is established that Tregs potently interfere with tumorspecific T cells (5)(6)(7)(8), their impact on innate immune cells, in particular, on myeloid cells, has been clearly less investigated in the context of tumor development (9,10).…”

Antigen Localization Controls T Cell-Mediated Tumor Immunity

“…For a nonimmunogenic tumor, such as MCA, Tregs clearly play an important role, and introduction of an immunogenic protein per se could not prevent or even delay outgrowth of the tumor, unless it was secreted as a vesicle-bound form. Moreover, Tregs in this same MCA model secreting sOVA were shown to kill dendritic cells in an OVA-specific manner; thus, in addition to direct suppression, they indirectly blocked the formation of a strong OVAspecific T cell-mediated immune response (25). We did not find differences in the percentage of total dendritic cells (I.S.…”

“…However, Tregs are important for the outcome of the immune response in this tumor model, because we showed previously that the addition of more OVAspecific naive CD8 + OT-I T cells alone was not sufficient to prevent growth of the sOVA tumor (15). Only when the Tregs were depleted in the sOVA tumor could OT-I T cells induce regression of the tumor, showing that Tregs are important in this tumor model (25). It is of note that Tregs suppress in an Ag-independent manner (Fig.…”

“…Tregs exert a strong, suppressive activity on multiple components of the immune system. Depending on the model, they can suppress priming or proliferation of the T cells, inhibit proliferation, or even kill dendritic cells in an Ag-specific manner (23,25). In general, the influx of CD8 + T cells is assumed to be beneficial for the patient, whereas a higher Treg number in the tumor implies a worse prognosis (26).…”

Cross-Talk of Breast Cancer Cells with the Immune System

“…Increased accumulation of Treg cells is also seen in sentinel lymph nodes of breast cancer patients and it correlates with the size of the primary tumor (Gupta et al, 2011). Since anti-tumor T cells are activated in sentinel lymph nodes (Kim et al, 2006) the increased Treg cell presence might limit the efficacy of preoperative chemotherapy for locally advanced breast cancer by inhibiting the activation of tumor-specific T cells (Boissonnas et al, 2010). Multiple additional strategies for manipulating the immune environment of breast cancer are being studied, including TLR agonists (Lu et al, 2010), immunomodulatory drugs and vaccines (Emens et al, 2009).…”