In parallel, activated STAT3 can also promote IL6 gene expression, resulting in a feed-forward autocrine feedback loop ( 20). Importantly, elevated levels of systemic and pulmonary IL6 are associated with poor survival of patients with non–small cell lung cancer (NSCLC refs. Elevated levels of IL6 or activated STAT3 have been observed in chronic inflammatory tissues and many solid tumors ( 17). IL6 activates JAK/STAT3 signaling by binding its receptor, and subsequently dimerizes with its coreceptor gp130, followed by recruitment of cellular signaling proteins, including JAKs and STAT3 ( 14–16). IL6, a cytokine of the chemokine family, is widely expressed in a variety of immune cells and malignant tumors including lung cancer ( 11–13). Because most of studies on EMT and metastasis are based on the analyses in vitro and/or in immune-deficient nude mice, the interplay between EMT-like traits of tumor cells and host immunity in metastasis remains poorly characterized. These observations provide a functional link between metastatic potential and immunosuppressive traits. Recently, cancer cells undergoing EMT process were found to acquire immunosuppressive functions during metastasis ( 7, 8). Cancer cells may thus be reprogrammed to become invasive and immunosuppressive during the process. On one hand, proinflammatory cytokines in microenvironment can induce cancer cells to program epithelial-to-mesenchymal transition (EMT), a key step of the metastatic process ( 4, 5) on other hand, cancer cells can release factors or cytokines to recruit immunosuppressive lymphocytes, which facilitate the metastatic niche formation ( 6). The processes of metastasis are driven by the interplay between cancer cells and the metastasis-supportive microenvironment ( 3). Tumor metastasis is a complex process consisting of multiple steps, involving dissemination of cancer cells to local and distant organ sites, and their adaptation to new environments ( 1, 2). Significance: IL6 plays important roles not only in cell autonomous propensity for metastasis, but also in establishing the metastatic niche. Therefore, IL6/STAT3 signaling is crucial for orchestrating premetastatic niche formation and immunosuppression in lung. Consistently, IHC staining showed that activated STAT3 correlated with repressed infiltration of CD8 + T cells in non–small cell lung cancer.
Mechanistically, dysregulated IL6 reprogrammed the STAT3 pathway in metastatic tumor cells, and induced recruitment of myeloid-derived suppressor cells and polarized macrophages to evade host immunity. Depletion of IL6 via combined deletion of Il6 and Gprc5a genes almost completely eliminated lung metastasis in Gprc5a-ko/ Il6-ko ( 5a −/− Il6 −/−) mice. Noticeably, lung metastasis was greatly increased in Gprc5a-knockout (ko 5a −/−) mice compared with wild-type mice, which correlated with upregulated IL6 in the tumor microenvironment. Thus, STAT3-mediated immunosuppression is crucial for metastasis. Consistently, repression of STAT3 signaling in tumor cells made them susceptible to T-cell–mediated cytotoxicity. Here, we showed that blockade of intrinsic STAT3 signaling in lung tumor cells suppressed lung metastasis in immune-competent syngeneic mice, but not in immune-deficient nude mice.
IL6/STAT3 signaling is aberrantly activated in lung tumorigenesis and metastasis, however, the roles and mechanisms of action of IL6 remain controversial. This is facilitated by metastatic niches that are either postformed through reciprocal signaling between tumor cells and local stromal cells or preformed as premetastatic niches before tumor cell arrival. Cancer cells that succeed in forming metastasis need to be reprogrammed to evade immune surveillance and survive in a new microenvironment.
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