MIF-CD74 signaling impedes microglial M1 polarization and facilitates brain tumorigenesis

Ghoochani, Ali; Schwarz, Marc; Yakubov, Eduard; Engelhorn, Tobias; Doerfler, Arnd; Buchfelder, Michael; Bucala, Richard; Savaskan, Nicolai Ε.; Eyüpoglu, Ilker Y.

doi:10.1038/onc.2016.160

Cited by 111 publications

(104 citation statements)

References 51 publications

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“…33 Even our finding that MIF drives M1 TAM polarization, while consistent with reports in adipose cells in MIF knockout mice 34 and a study correlating glioblastoma TAM expression of MIF receptor CD74 with M1 polarization, 35 must be resolved with reports suggesting that MIF can drive pro-tumoral M2 macrophage polarization. 18, 36 …”

Section: Discussionmentioning

confidence: 99%

Macrophage migration inhibitory factor downregulation: a novel mechanism of resistance to anti-angiogenic therapy

et al. 2017

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Anti-angiogenic therapies for cancer such as VEGF neutralizing antibody bevacizumab have limited durability. While mechanisms of resistance remain undefined, it is likely that acquired resistance to anti-angiogenic therapy will involve alterations of the tumor microenvironment. We confirmed increased tumor-associated macrophages in bevacizumab-resistant glioblastoma patient specimens and two novel glioblastoma xenograft models of bevacizumab resistance. Microarray analysis suggested downregulated macrophage migration inhibitory factor (MIF) to be the most pertinent mediator of increased macrophages. Bevacizumab-resistant patient glioblastomas and both novel xenograft models of resistance had less MIF than bevacizumab-naïve tumors, and harbored more M2/protumoral macrophages that specifically localized to the tumor edge. Xenografts expressing MIF-shRNA grew more rapidly with greater angiogenesis and had macrophages localizing to the tumor edge which were more prevalent and proliferative, and displayed M2 polarization, whereas bevacizumab-resistant xenografts transduced to upregulate MIF exhibited the opposite changes. Bone marrow-derived macrophage were polarized to an M2 phenotype in the presence of condition-media derived from bevacizumab-resistant xenograft-derived cells, while recombinant MIF drove M1 polarization. Media from macrophages exposed to bevacizumab-resistant tumor cell conditioned media increased glioma cell proliferation compared to media from macrophages exposed to bevacizumab-responsive tumor cell media, suggesting that macrophage polarization in bevacizumab-resistant xenografts is the source of their aggressive biology and results from a secreted factor. Two mechanisms of bevacizumab-induced MIF reduction were identified: (1) bevacizumab bound MIF and blocked MIF-induced M1 polarization of macrophages; and (2) VEGF increased glioma MIF production in a VEGFR2-dependent manner, suggesting that bevacizumab-induced VEGF depletion would downregulate MIF. Site-directed biopsies revealed enriched MIF and VEGF at the enhancing edge in bevacizumab-naïve patients. This MIF enrichment was lost in bevacizumab-resistant glioblastomas, driving a tumor edge M1-to-M2 transition. Thus, bevacizumab resistance is driven by reduced MIF at the tumor edge causing proliferative expansion of M2 macrophages, which in turn promotes tumor growth.

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Section: Discussionmentioning

confidence: 99%

Macrophage migration inhibitory factor downregulation: a novel mechanism of resistance to anti-angiogenic therapy

et al. 2017

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“…A total of 200 000 cells per well were seeded in 6-well plate and drug treatment was applied for 24 and 72 h. 41 Cells and media supernatants were collected as described before. 29 Briefly, cells were washed with PBS and fixed with 70% ethanol solution overnight at 4 °C.…”

Section: Methodsmentioning

confidence: 99%

ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner

et al. 2017

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Activating transcription factor 4 (ATF4) is a critical mediator of metabolic and oxidative homeostasis and cell survival. ATF4 is elevated in response to diverse microenvironmental stresses, including starvation, ER stress damages and exposure to toxic factors. Here we show that ATF4 expression fosters the malignancy of primary brain tumors (WHO grade III and IV gliomas) and increases proliferation and tumor angiogenesis. Hence, ATF4 expression promotes cell migration and anchorage-independent cell growth, whereas siRNA-mediated knockdown of ATF4 attenuates these features of malignancy in human gliomas. Further experiments revealed that ATF4-dependent tumor promoting effects are mediated by transcriptional targeting the glutamate antiporter xCT/SCL7A11 (also known as system Xc-). Thus, xCT is elevated as a consequence of ATF4 activation. We further found evidence that ATF4-induced proliferation can be attenuated by pharmacological or genetic xCT inhibition and ferroptosis inducers such as sorafenib, erastin and GPx4 inhibitor RSL3. Further, fostered xCT expression promotes cell survival and growth in ATF4 knockdown cells. Moreover, increased xCT levels ameliorate sorafenib and erastin-induced ferroptosis. Conversely, ATF4 knockdown renders cells susceptible for erastin, sorafenib and RSL3-induced ferroptosis. We further identified that ATF4 promotes tumor-mediated neuronal cell death which can be alleviated by xCT inhibition. Moreover, elevated ATF4 expression in gliomas promotes tumor angiogenesis. Noteworthy, ATF4-induced angiogenesis could be diminished by ferroptosis inducers erastin and by GPx4 inhibitor RSL3. Our data provide proof-of-principle evidence that ATF4 fosters proliferation and induces a toxic microenvironmental niche. Furthermore, ATF4 increases tumor angiogenesis and shapes the vascular architecture in a xCT-dependent manner. Thus, inhibition of ATF4 is a valid target for diminishing tumor growth and vasculature via sensitizing tumor cells for ferroptosis.

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“…Strikingly, when comparing the gene expression of six mUM patients with that of one human disease-free liver normal biopsy (normal liver, NL), most mUM patients displayed upregulation of specific immune genes related to suppression of cytolytic T cells (CTLs) ( Figure 3C), including HLA-DRA, LGALS3, and CD38 partially [30][31][32][33][34][35][36][37][38]; ICRs such as TIM-3 (HAVCR2), HMGB1, IDO1, LAG3, and CD73 (NT5E) [39][40][41][42][43][44]; and TAM functional markers, such as ANXA1, CD74, CD9, INFAR2, MIF, PLA2G6, and CD163 [36,45,46]. In addition, transcript levels of NOS2, a predominant M1 macrophage marker [47], were similar to the levels found in normal liver without tumours.…”

Section: Bap1 Loss Correlates With Immunosuppressive Network In Pummentioning

confidence: 99%

Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development

Figueiredo

Kalirai

Sacco

et al. 2020

The Journal of Pathology

109

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Immunotherapy using immune checkpoint inhibitors (ICIs) induces durable responses in many metastatic cancers. Metastatic uveal melanoma (mUM), typically occurring in the liver, is one of the most refractory tumours to ICIs and has dismal outcomes. Monosomy 3 (M3), polysomy 8q, and BAP1 loss in primary uveal melanoma (pUM) are associated with poor prognoses. The presence of tumour‐infiltrating lymphocytes (TILs) within pUM and surrounding mUM – and some evidence of clinical responses to adoptive TIL transfer – strongly suggests that UMs are indeed immunogenic despite their low mutational burden. The mechanisms that suppress TILs in pUM and mUM are unknown. We show that BAP1 loss is correlated with upregulation of several genes associated with suppressive immune responses, some of which build an immune suppressive axis, including HLA‐DR, CD38, and CD74. Further, single‐cell analysis of pUM by mass cytometry confirmed the expression of these and other markers revealing important functions of infiltrating immune cells in UM, most being regulatory CD8+ T lymphocytes and tumour‐associated macrophages (TAMs). Transcriptomic analysis of hepatic mUM revealed similar immune profiles to pUM with BAP1 loss, including the expression of IDO1. At the protein level, we observed TAMs and TILs entrapped within peritumoural fibrotic areas surrounding mUM, with increased expression of IDO1, PD‐L1, and β‐catenin (CTNNB1), suggesting tumour‐driven immune exclusion and hence the immunotherapy resistance. These findings aid the understanding of how the immune response is organised in BAP1 − mUM, which will further enable functional validation of detected biomarkers and the development of focused immunotherapeutic approaches. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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MIF-CD74 signaling impedes microglial M1 polarization and facilitates brain tumorigenesis

Cited by 111 publications

References 51 publications

Macrophage migration inhibitory factor downregulation: a novel mechanism of resistance to anti-angiogenic therapy

Macrophage migration inhibitory factor downregulation: a novel mechanism of resistance to anti-angiogenic therapy

ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner

Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development

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