We have found that breast cancer lung metastasis is actively facilitated by Tregs, as in their absence, the inherent capability of tumors alone to migrate into inflamed lungs was not sufficient to establish lung metastasis (Olkhanud et al., 2009). Lung metastasis required an active participation of CCR4+ Tregs. The biological role of Tregs was to infiltrate lungs together with tumor cells to regulate or even kill anti-tumor NK cells. This presumably explains our finding that NK cell counts were significantly reduced in peripheral blood (PB) of both tumor-bearing mice and human patients with an advanced stage IV breast cancer. Thus, strategies that abrogate any part of this process, such as targeted inactivation of CCR4+ cells or direct depletion of Tregs, would be expected to improve the outcome of the disease. This in turn would activate both antitumor innate and adaptive immune responses through activation of NK cells and cytolytic T cells. Interestingly, the Tregs killed NK cells by utilizing beta-galactoside-binding protein (bGBP), the same lectin-type factor shown by our group to regulate the maintenance and control of peripheral tolerance by inducing non-cytotoxic TCR signaling of CD8+ T cells (Baatar et al., 2009). Despite this, Tregs may not to be a sole cell type that promotes lung metastasis. We have recently found that breast cancer cells control the Treg expansion utilizing previously unknown regulatory immune cell-mediated mechanism. To do this, cancer cells first targeted B cells to evoke the conversion of normal B cells into a poorly proliferative regulatory CD19+ CCR6+ CD25High B7-H1 High CD86 High CD62LowIgMInt/Low cells that express constitutively-active Stat3. The primary function of these cells, designated tumor-evoked Bregs (tBregs), was to induce conversion of FoxP3+ Tregs from resting CD4+ T cells. In fact, our data can be considered as the first proof of cancer-associated Bregs. This work was recently published in Cancer Research (Olkhanud et al., 2011). The clinical implications of our findings are that, to effectively combat cancer and cancer metastasis, tBregs have to be controlled to interrupt the initiation of cancer-induced suppressive events. In addition, considering the assumption that cancer usually hijacks the existing machinery of immune regulation, tBregs may be a part of normal immune function that prevents the induction of autoimmune responses. As such, their impairment may explain the age-related incidences of autoimmune diseases and poor vaccine responses in elderly. The preliminary results from ongoing studies in my laboratory support this hypothesis.
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