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  • Aspects of the immune system can contribute to


    Aspects of the immune system can contribute to tumor growth and development. High levels of circulating IL-6 is associated with a poor prognosis in lung cancer patients [3]. IL-6 signaling is propagated through the STAT1/3 pathways [4]. Activation of the signal transducer and activator of transcription (STAT) and extracellular signal-regulator Kinase (ERK) pathways in peripheral blood Quizartinib (AC220) can produce anti-tumor activity, and defective STAT1/3 signaling in peripheral blood T cells has been suggested as a poor prognostic indicator in breast cancer [5]. Although a variety of demographic features have been associated with high levels of circulating IL-6, i.e. age, smoking history, and chemotherapy, it remains unclear whether circulating IL-6 is a cause or a consequence of poor survival because possible mechanisms have not been elucidated [6]. Stromal and tumor-derived IL-6 can enhance the survival and proliferation of tumor cells, however, it is not known how circulating IL-6 could affect tumor populations. We proposed that a possible mechanism could be that circulating IL-6 may alter T cell populations or signaling to suppress the immune system and ultimately support tumor growth. We explored this possible relationship by characterizing T cell populations and signaling in advanced NSCLC patients with high and low circulating IL-6 levels.
    Materials and methods
    Discussion Circulating IL-6 has frequently been associated with a poor prognosis in cancer patients, and while IL-6 has been linked to various demographic and behavioral characteristics, i.e. age, smoking history…, it remains unclear whether circulating IL-6 directly affects survival or if it is a consequence of poor survival [6]. We characterized T cell populations and signal in patients with high levels or circulating IL-6 and determined that these patient have altered features relative to those with low levels of circulating IL-6. We found that NSCLC patients with low levels of circulating IL-6 had T cell characteristics, PD-1 expression and STAT1/STAT3 responses, similar to those reported for normal donors, while those with high circulating IL-6 had markers associated with poor prognosis including elevated PD-1 expression and muted STAT1 signaling [7]. Those patients in with the poor prognostic indicators, PD-1 expression, and STAT1 signaling, were those that had the shortest survival in our cohort. The changes we observed in patients with high circulating IL-6 are associated with immune suppression and poor prognosis in cancer patients. Lymphocytes from tumor-bearing mice were found to have muted Stat1 and Stat3 phosphorylation compared to those without tumors, which was related to a decrease in immune function in these animals [8]. STAT1 is also required for T cell clonal expansion [9]. T-cell expression of PD-1 can inhibit the immune response and is associated with poor survival in NSCLC patients [7]. Our results suggest that T cell-suppression in a possible mechanism for how high levels of circulating IL-6 can promote tumor progression. We were able to directly link the poor survival associated with high levels of circulating IL-6 to impaired STAT1 signaling and PD-1 expression to suppress the immune system. This work highlights the effect that circulating IL-6 has on peripheral blood T cells, however, the tumor microenvironment may also contribute to disease progression and shorter survival. Tumor progression can stimulate immune and stromal cells to secrete IL-6 [10]. Additionally, IL-6 can be secreted directly by tumor cell [11]. Regardless of the source, IL-6 can facilitate tumor proliferation and immune invasion [11]. We believe the alterations seen in the peripheral blood T cells are also present in the tumor, and, therefore, IL-6-associated T cell dysfunction may occur in the tumor, which could promote tumor progression and poor survival [12].