Granulopoietic Growth Factor Secretion in Ovarian Carcinoma as a Mechanism for the Emergence of Immune Suppressive Myeloid Subsets.

摘要

Among prominent mechanisms thought to impede the anticancer response is the accumulation of pro-tumor myeloid populations. However, there is a fundamental gap regarding the mechanisms that drive their accumulation. To that end, we originally hypothesized that tumor-derived granulocyte-colony stimulating factor (G-CSF) production in ovarian cancer facilitates this aberrant myelopoietic response. However, during year-1, we made the discovery implicating tumor-derived IL-8 in the mechanism of ovarian cancer-mediated immune suppression. Accordingly, this observation prompted us to further evaluate the potential clinical significance of IL-8. To do so, we analyzed the relationship between blood IL-8 levels and newly acquired de-identified patient survival data and, unfortunately, found no significant connection between these clinical factors. Consequently, we reassessed the potential clinical merit of five other myelopoietic factors we had previously identified. Interestingly, only IL-6 fulfilled three important clinical criteria. Altogether, we found that the levels of IL-6: (1) were significantly higher in patients than matched healthy donors; (2) strongly correlated with the accumulation of myeloid populations commonly observed in ovarian cancer patients; and (3) were inversely associated with patient outcome; that is, rising IL-6 levels portended worse overall survival. Although the tumor factor identified is different from the original premise, the conceptual advances made are still consistent with the original hypothesis.