Interferon signaling in ascites-associated macrophages is linked to a favorable clinical outcome in a subgroup of ovarian carcinoma patients

Abstract

BackgroundAlthough tumor-associated macrophages (TAMs) are essential for cancer progression, connections between different clinical outcomes and transcriptional networks have not been reported. We have addressed this issue by analyzing global expression patterns of TAMs isolated from the ascites of ovarian cancer patients.ResultsTAMs isolated from different ovarian cancer patients can be stratified by coexpression or principal component analysis into subgroups with specific biological features and associated with distinct clinical outcomes. A hallmark of subgroup A is a high expression of clinically unfavorable markers, including (i) high CD163 expression, a surface receptor characteristic of an anti-inflammatory activation state, (ii) increased PCOLCE2 expression, indicative of enhanced extracellular matrix organization, and (iii) elevated ascites levels of IL-6 and IL-10, linked to the aggressiveness of ovarian cancer and immune suppression. In contrast, subgroup B TAMs are characterized by the upregulation of genes linked to immune defense mechanisms and interferon (IFN) signaling. Intriguingly, analysis of published data for 1763 ovarian cancer patients revealed a strong association of this transcriptional signature with a longer overall survival. Consistent with these results, IFNγ was able to abrogate the suppressive effect of ovarian cancer ascites on the inducibility of IL12B expression and IL-12 secretion, a key determinant of a cytotoxic immune response.ConclusionsThe survival of ovarian cancer patients is linked to the presence of TAMs with a transcriptional signature that is characterized by a low expression of protumorigenic and immunosuppressive markers and an upregulation of genes linked to interferon signaling. The observed IFNγ-mediated restoration of the inducibility of IL-12 in the presence of ascites provides a possible explanation for the association of an interferon signaling-associated signature with a favorable clinical outcome.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3630-9) contains supplementary material, which is available to authorized users.

Tumor-associated macrophages promote ovarian cancer cell migration by secreting transforming growth factor beta induced (TGFBI) and tenascin C

“…Among these, three proteins are migration-promoting candidates as suggested by literature data [28][29][30] , i.e., TGFBI, TNC, and FN1 (Table 1). A similar observation was made for macrophage mannose receptor 1 (MRC1, CD206) and scavenger receptor cysteine-rich type 1 protein (CD163), which are known to be commonly upregulated in TAM and alternatively activated macrophages 8,17,25 , and thus serve as plausibility controls.…”

“…TAMs constitute a prominent cell population in ascites known to promote tumor growth, metastasis, and immunosuppression [14][15][16] . TAMs are reprogrammed by factors of the TME to adopt a pro-tumorigenic and immunosuppressive phenotype, which is linked to a poor clinical outcome 8,13,17,18 . TAMs contribute to the tumor secretome by releasing a plethora of soluble mediators, such as interleukin (IL)-6, IL-10, C-C chemokine motif ligand 18 (CCL18), CCL22, tumor necrosis factor α, and transforming growth factor beta (TGFβ), that trigger protumorigenic signaling pathways in both tumor and host cells of the TME [19][20][21] .…”

Cross‐talk between ovarian cancer cells and macrophages through periostin promotes macrophage recruitment

“…Malignant ascites often contain a large number of TAMs, which are correlated with poor prognosis in ovarian cancer patients. 8,27 However, the mechanism by which TAMs accumulate in the tumor microenvironment remains unclear. In the present study, we found that high levels of POSTN existed in malignant ascites and were correlated with CD163 + TAMs.…”

Role of the body mass index in the genesis of ascites in ovarian cancer: a forensic case and review of the literature

“…In one study, a group of patients, characterised by upregulation of gene expression of IFN-gamma, showed a longer survival. High IFN-gamma levels, in fact, affect (abrogate-block) IL-12 inhibition by malignant ascites, with a favourable outcome 14. It has been shown that by combining the surgical state and the IL-17 and IL-21 levels in the ascitic fluid, a risk score for predicting the outcome of the patient may be obtained 15.…”