Toll-like receptor (TLR) expression and function of immune system cells from metastatic breast cancer patients with circulating tumor cells

The National Cancer Institute estimates that a U.S. woman's lifetime risk of developing breast cancer is approximately 12%. Thus, the risk posed by breast cancer represents a complex interplay between host and tumor immunity, which is affected by a number of factors, some of which have yet to be enumerated. Factors affecting the development of breast tumors include: the microenvironment of neoplasm, host immune system function, and genetic susceptibility. Chronic inflammatory states are considered to favor an increased predisposition to cancer, with continuous activation of inflammatory cytokines and other hallmarks of inflammation exerting a deleterious effect.;Toll-like receptors (TLRs) are members of the innate immune system and are an important link to adaptive immunity through their signaling mechanisms. TLRs are stimulated upon recognition of their specific ligand, and depending on the TLR, a specific pathway is activated, which results in translation of transcription factors, which generally function to attract host immune cells. However, the good intentions of TLRs are sometimes not transferred to positive long-term effects, due to their involvement in exacerbating inflammatory effects and even contributing to continued inflammation. Therefore, it is useful to think of TLR immunity as a continuous spectrum which covers foreign pathogens as well as viral and tumorigenic sources. It then becomes more apparent that which TLRs represent an attractive strategy to utilize in stimulating an immune response; they can further function in a way that is ultimately harmful to the host. Consequently, TLR function can have both positive and negative effects, and both of these pathways should be explored in the future treatment of disease. Circulating tumor cells (CTCs) are neoplastic cells present in the circulation that have been found to be an indicator of disease progression and long-term survival. Furthermore, TLR 2 and 4 expression and host immune function were investigated by the stimulation of TLRs with their ligands and assessment of cytotoxic responsiveness by host natural killer (NK) cells.;Flow cytometric data showed significant differences between circulating tumor cell (CTC) positive patients and CTC negative patients in their expression of TLR2+ by CD8+ T cells (p = 0.048), TLR2+ by CD11c+ monocytic dendritic cells (p = 0.026), TLR4+ by CD11c+ monocytic cells (p = 0.00), TLR3+ by CD11c+ cells (p = 0.008), and TLR8+ by CD11c+ cells (p = 0.044) when analyzed by independent t tests using SPSS software. CTC positive patients expressed decreased TLR2+ CD8+ T cells and increased CD11c+ monocytic cells compared to their negative counterparts.;Functional analyses were determined by percent specific lysis calculation after patient cells, either left unstimulated or stimulated with either lipopolysaccharide (LPS) or histone proteins, were incubated with K562 target cells labeled with Cr51. Tukey analysis showed significant differences between CTC positive and CTC negative samples when unstimulated, or LPS-stimulated (p = 0.001) and marginally significant results (p = 0.009) between histone- stimulated samples. The increased expression of CD11c and TLRs may indicate important links to long-term adaptive immunity; however, the CTC positive group showed the least cytotoxic response, which may further indicate vulnerability to tumorigenesis.