Mixed‐polarization phenotype of ascites‐associated macrophages in human ovarian carcinoma: Correlation of CD163 expression, cytokine levels and early relapse

Reinartz, Silke; Schumann, Tim; Finkernagel, Florian; Wortmann, Annika; Jansen, Julia M.; Meißner, Wolfgang; Krause, Michael; Schwörer, Anne-Marie; Wagner, Uwe; Müller‐Brüsselbach, Sabine; Müller, Rolf

doi:10.1002/ijc.28335

Cited by 228 publications

(248 citation statements)

References 41 publications

(91 reference statements)

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“…It should also be noted that there are indications that the subdivision in M1 and M2 is not absolute. There are potentially intermediate stages regarding marker expression, cytokine production, functionality, 45,[48][49][50] and potentially sensitivity for hCD64 immunotoxins. This is clearly reflected in our in vitro experiments, in which we induce the different subpopulations.…”

Section: Discussionmentioning

confidence: 99%

Targeting CD64 mediates elimination of M1 but not M2 macrophages in vitro and in cutaneous inflammation in mice and patient biopsies

Hristodorov¹,

Mladenov²,

Felbert³

et al. 2015

mAbs

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(2015) Targeting CD64 mediates elimination of M1 but not M2 macrophages in vitro and in cutaneous inflammation in mice and patient biopsies, mAbs, 7:5, 853-862, DOI: 10.1080/19420862.2015 To link to this article: https://doi.org/10. 1080/19420862.2015 (classical M1 or alternative M2), that play a differential role in immune regulation. In general, the M1 contribute to onset of inflammation, whereas the M2 orchestrate resolution and repair, whereby failure to switch from predominantly M1 to M2 reinforces a pro-inflammatory environment and chronic inflammation. Here, we show selective elimination of M1 macrophages in vitro by a range of CD64-targeted immunotoxins, including H22 (scFv)-ETA'. After re-polarization of already polarized macrophages, still only M1 polarization showed sensitivity toward CD64-directed immunotoxins. The selectivity for M1 was found linked to reduced endosomal protease activity in M1 macrophages as demonstrated by inhibition of endosomal proteases. Using the H22(scFv)-ETA' in a transgenic mouse model for chronic cutaneous inflammation, the M1 specificity was confirmed in vivo and a beneficial effect on inflammation demonstrated. Also ex vivo on skin biopsies from atopic dermatitis and diabetes type II patients with chronically-inflamed skin, a clear M1 specific effect was found. This indicates the potential relevance for human application. Our data show that targeting M1 macrophages through CD64 can be instrumental in developing novel intervention strategies for chronic inflammatory conditions.

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Section: Discussionmentioning

confidence: 99%

Targeting CD64 mediates elimination of M1 but not M2 macrophages in vitro and in cutaneous inflammation in mice and patient biopsies

Hristodorov¹,

Mladenov²,

Felbert³

et al. 2015

mAbs

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“…18 A high level of IL-6 in the tumor microenvironment may attract and differentiate macrophages into subtypes that in their turn produce more IL-6, creating an immunosuppressive environment. Recently, Reinartz et al 41 defined a subgroup of ovarian cancer patients with a poor clinical outcome, these patients displayed a high CD163 expression and high IL-6 levels in ascites.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 receptor and its ligand interleukin-6 are opposite markers for survival and infiltration with mature myeloid cells in ovarian cancer

et al. 2014

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y These authors contributed equally to this study.Keywords: epithelial ovarian cancer, IL-6, interleukin-6; IL-6R, interleukin-6 receptor, pSTAT3, tumor-infiltrating myeloid cells Abbreviations: DSS, disease-specific survival; EOC, epithelial ovarian cancer; IL-6R, interleukin-6, IL-6, interleukin-6 receptor; FIGO, International Federation of Gynecology and Obstetrics; MDSC, myeloid-derived suppressor cell; pSTAT3, phosphorylated signal transducer and activator of transcription 3; T reg, regulatory T cell; TMA, tissue microarray; TAM, tumor-associated macrophage; TIL, tumor-infiltrating lymphocytes; TIM, tumor-infiltrating myeloid cellAn increased level of interleukin-6 (IL-6) in epithelial ovarian cancer (EOC) is correlated with a worse prognosis. IL-6 stimulates tumor-growth and inflammation. We investigated the intricate interaction between the IL-6 signaling pathway and tumor-infiltrating myeloid cells (TIMs) to determine their prognostic impact in EOC. 160 EOC samples were analyzed for the expression of IL-6, its receptor (IL-6R) and downstream signaling via pSTAT3 by immunohistochemistry. Triple color immunofluorescence confocal microscopy was used to identify myeloid cell populations by CD14, CD33, and CD163. The relationship between these markers, tumor-infiltrating immune cells, clinical-pathological characteristics and survival was investigated. EOC displayed a dense infiltration with myeloid cells, in particular of the CD163 C type. The distribution pattern of all myeloid subtypes was comparable among the different histological subtypes. Analysis of the tumor cells revealed a high expression of IL-6R in 15% and of IL-6 in 23% of patients. Interestingly, tumors expressing IL-6 or IL-6R formed two different groups. Tumors with a high expression of IL-6R displayed low mature myeloid cell infiltration and a longer disease-specific survival (DSS), especially in late stage tumors. High expression of IL-6R was an independent prognostic factor for survival by multivariate analyses (hazard ratio D 0.474, p D 0.011). In contrast, tumors with high epithelial IL-6 expression displayed a dense infiltration of mature myeloid cells and were correlated with a shorter DSS. Furthermore, in densely CD8 C T-cell infiltrated tumors, the ratio between these lymphoid cells and CD163 C myeloid cells was predictive for survival. Thus, IL-6 and IL-6R are opposite markers for myeloid cell infiltration and survival.

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“…In addition to the microenvironment within tumor tissues, TAMs are also distributed in some special organs and lymph nodes, associated with metastasis to these regions (13,14). TAMs infiltrate into OC tissues in large numbers (15)(16)(17), contributing to the progression of OC (18,19), thus negatively affecting the progression-free survival rates and overall survival rates of these patients (16). However, the precise mechanism of how TAMs contribute to the progression of OC remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of IGF1 by tumor-associated macrophages promotes the proliferation and migration of epithelial ovarian cancer cells

Liu

Wang

et al. 2017

Oncol Rep

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Abstract. Ovarian cancer (OC), of which epithelial ovarian cancer (EOC) is the most common, is the deadliest gynecological tumor because of the difficulties in detection at early stages, and metastasis and chemoresistance at advanced stages. Tumor-associated macrophages (TAMs) differentiate through alternative pathways and play important roles in tumor growth and metastasis. However, the underlying mechanism remains unclear. Here, we established a mouse TAM model using bone marrow monocytes and conditioned medium (CM) of TAMs to culture ID8 mouse EOC cells. The results showed that TAM CM accelerated the proliferation and migration of ID8 cells. In a previous study, gene chip analysis showed that human TAMs expressed significantly higher levels of insulinlike growth factor-1 (IGF1) than undifferentiated M0 myeloid cells. In the present study, we observed that the IGF1 level was higher in human EOC specimens than that in benign ovarian tumor specimens, and further analysis showed that a higher level of IGF1 was related to more advanced clinical stage and liver metastasis. Therefore, we hypothesized that TAMs may accelerate the proliferation and migration of EOC cells by upregulating IGF1. As expected, increased IGF1 expression at both the mRNA and protein levels was observed in ID8 cells cultured with TAM CM, whereas blockade of the IGF1 pathway in ID8 cells with an IGF1 neutralizing antibody effectively reversed the promotion of proliferation and migration. Finally, we inhibited the phosphorylation of insulin-like growth factor-1 receptor (IGF1R) and its downstream molecules Akt and Erk with the IGF1R inhibitor linsitinib, and observed that the treatment effectively suppressed the proliferation and migration of ID8 cells exposed to TAM CM. Thus, we demonstrated that TAMs may promote the growth and metastasis of EOC via the activation of the IGF1 pathway; thus, targeting the IGF1 pathway may be promising for EOC therapy.

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Mixed‐polarization phenotype of ascites‐associated macrophages in human ovarian carcinoma: Correlation of CD163 expression, cytokine levels and early relapse

Cited by 228 publications

References 41 publications

Targeting CD64 mediates elimination of M1 but not M2 macrophages in vitro and in cutaneous inflammation in mice and patient biopsies

Targeting CD64 mediates elimination of M1 but not M2 macrophages in vitro and in cutaneous inflammation in mice and patient biopsies

Interleukin-6 receptor and its ligand interleukin-6 are opposite markers for survival and infiltration with mature myeloid cells in ovarian cancer

Upregulation of IGF1 by tumor-associated macrophages promotes the proliferation and migration of epithelial ovarian cancer cells

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