MFG-E8–mediated uptake of apoptotic cells by APCs links the pro- and antiinflammatory activities of GM-CSF

Jinushi, Masahisa; Nakazaki, Yukoh; Dougan, Michael; Carrasco, Daniel R.; Mihm, Martín C.; Dranoff, Glenn

doi:10.1172/jci30966

Cited by 183 publications

(236 citation statements)

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“…Tim3 pathway inhibition reduces phagocytosis of apoptotic cells and induces autoantibody production, indicating the break of peripheral tolerance [12]. In concordance with this, the efficacy of a therapeutic vaccine for melanoma is significantly augmented when the phagocytosis of apoptotic cells is inhibited by the binding of milk fat globule epidermal growth factor 8 to phosphatidylserine [34].…”

Section: Discussionmentioning

confidence: 65%

The inhibition of the T-cell immunoglobulin and mucin domain 3 (Tim3) pathway enhances the efficacy of tumor vaccine

Lee

Woo

Heo

et al. 2010

Biochemical and Biophysical Research Communications

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Section: Discussionmentioning

confidence: 65%

The inhibition of the T-cell immunoglobulin and mucin domain 3 (Tim3) pathway enhances the efficacy of tumor vaccine

Lee

Woo

Heo

et al. 2010

Biochemical and Biophysical Research Communications

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“…Tregs dampen the activity of effector T cells, and thus prevent excessive immune reactions, such as autoimmunity, but they can also prevent efficient immune responses, especially in the context of tumors. Two recent articles have proposed a regulatory T cell-promoting role for Mfge8/lactadherin in mice: in atherosclerosis (Ait-Oufella et al, 2007), or in granulocyte monocyte-colony stimulating factor-dependent induction of anti-tumor immune responses (Jinushi et al, 2007). More recently, the latter group has shown that subcutaneous grafts of mouse melanoma cells transfected with Mfge8 were infiltrated with Mfge8-expressing macrophages, regulatory T cells, and poorly efficient cytotoxic T cells when transplanted in mice (Jinushi et al, 2008), and thus became more aggressive.…”

Section: Discussionmentioning

confidence: 99%

“…BCG instillation has been proposed to overcome the tolerance established in the tumor, and switch the immune system towards effective antitumor activity (Saint et al, 2001). Jinushi et al (Jinushi et al, 2007) have shown that, in the presence of pathogen-derived ligands and/or necrotic cells, phagocytosis of tumor cells by macrophages is performed in the absence of Mfge8 and results in effective anti-tumor immune responses, whereas in the absence of these stress conditions, the same phagocytosis performed through Mfge8 induces tolerogenic immune responses. As any bacteria, BCG bears pathogen ligands, and its instillation probably creates the stress conditions proposed to favor effector immune responses.…”

Section: Discussionmentioning

confidence: 99%

“…Like the macrophage markers, MS4A1 was significantly overexpressed in MFGE8-overexpressing tumors, whether total or only superficial carcinoma were considered (Po0.025, Wilcoxon test, data not shown), suggesting the possible presence of B lymphocytes in these tumors. In addition, as MFGE8-mediated phagocytosis of apoptotic tumor cells by macrophages has been shown to promote the differentiation of regulatory T cells (Tregs) (Jinushi et al, 2007(Jinushi et al, , 2008, we asked whether Tregs were present in the bladder tumors. FOXP3 is the transcription factor commonly used as a Treg marker, but the low signal of the probe sets for this gene in the Affymetrix expression data precluded their use to identify Tregs.…”

Section: Mfge8 Promotes Bladder Tumor Developmentmentioning

confidence: 99%

“…In Mfge8-deficient mice, impaired elimination of apoptotic cells leads to autoimmune symptoms in old animals (Hanayama et al, 2004), and mammary gland inflammation after repeated pregnancies in females (Atabai et al, 2005;Hanayama and Nagata, 2005). MFGE8-mediated phagocytosis of apoptotic cells by macrophages in vitro induces their secretion of regulatory T cell (Treg)-inducing cytokines, thus potentially promoting tolerogenic immune responses (Jinushi et al, 2007). Second, on endothelial cells, MFGE8/lactadherin binding to avb3/b5 integrins promotes vascular endothelial growth factor (VEGF)-induced survival and proliferation, leading to angiogenesis (Silvestre et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Milk fat globule—epidermal growth factor—factor VIII (MFGE8)/lactadherin promotes bladder tumor development

Sugano

Bernard‐Pierrot

et al. 2010

Oncogene

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Milk fat globule-epidermal growth factor-factor VIII (MFGE8), also called lactadherin or SED1, is a secreted integrin-binding protein that promotes elimination of apoptotic cells by phagocytes leading to tolerogenic immune responses, and vascular endothelial growth factor (VEGF)-induced angiogenesis: two important processes for cancer development. Here, by transcriptomic analysis of 228 biopsies of bladder carcinomas, we observed overexpression of MFGE8 during tumor development, correlated with expression of genes involved in cell adhesion or migration and in immune responses, but not in VEGF-mediated angiogenesis. To test whether MFGE8 expression was instrumental in bladder tumor development, or a simple consequence of this development, we used genetic ablation in a mouse model of carcinogen-induced bladder carcinoma. We showed that Mfge8 was also upregulated in mouse carcinoma, and that in its absence, Mfge8-deficient animals developed less advanced tumors. Angiogenesis was similar in carcinogen-treated Mfge8-expressing or -deficient bladders, thus ruling out a major role of the proangiogenic function of Mfge8 for its protumoral role. By contrast, the tumorpromoting role of Mfge8 was not observed anymore in mice devoid of adaptive immune system, and human tumors overexpressing MFGE8 where invaded with macrophages and regulatory T cells, thus suggesting that MFGE8/ lactadherin favors development of bladder tumors at least partly by an immune system-dependent mechanism. Our observations suggest future use of MFGE8-inhibiting molecules as therapies of bladder carcinomas, and of a limited number of other human cancers, in which our analysis of public databases also revealed overexpression of MFGE8.

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Ipilimumab Plus Sargramostim vs Ipilimumab Alone for Treatment of Metastatic Melanoma

Hodi

Lee

McDermott

et al. 2014

JAMA

313

249

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Importance Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockade with ipilimumab prolongs survival in metastatic melanoma patients. CTLA-4 blockade and granulocyte-macrophage colony stimulating factor (GM-CSF) secreting tumor vaccine combinations demonstrate therapeutic synergy in pre-clinical models. A key issue is whether systemic GM-CSF synergizes with CTLA-4 blockade. Objective To compare the effect of sargramostim plus ipilimumab vs ipilimumab alone on overall survival in patients with metastatic melanoma. Design, Setting, and Participants A phase II randomized clinical trial was conducted in the United States by Eastern Cooperative Oncology Group between December 28, 2010 and July 28, 2011. Patients with unresectable stage III or IV melanoma, ≥one prior therapy, no CNS metastases, and ECOG performance status 0/1 were eligible. Interventions Patients were randomized to ipilimumab 10 mg/kilogram intravenously day 1 plus sargramostim 250 μg subcutaneously days 1-14 of 21 day cycles versus ipilimumab alone. Ipilimumab treatment included induction for four cycles followed by maintenance every fourth cycle. Main Outcomes and Measures Primary was comparison of the length of overall survival. Secondary was progression-free survival, response rate, safety, and tolerability. Results A total of 245 patients were treated. Median follow-up was 13.3 months (range; .03-19.9). Median overall survival for sargramostim plus ipilimumab was 17.5 months (95% CI; 14.9, not reached) compared to 12.7 months (95% CI; 10.0, not reached) for ipilimumab. One-year survival rate for sargramostim was 68.9% (95% CI; 60.6%, 85.5%) compared to 52.9% (95% CI; 43.6%, 62.2%) with ipilimumab (stratified logrank one-sided P=.01; mortality hazard ratio .64, one-sided 90% repeated CI (not applicable, .90)). A planned interim analysis was conducted at 69.8% (104 observed/ 149 planned deaths) information time. O'Brien-Fleming boundary was crossed for improvement in overall survival. There was no difference in progression-free survival. Median progression free survival for ipilimumab+sargramostim was 3.1 months (95% CI; 2.9, 4.6) and for ipilimumab was 3.1 months (95% CI; 2.9, 4.0). Grade 3-5 adverse events occurred in 44.9% (95% CI; 35.8%, 54.4%) of sargramostim plus ipilimumab and 58.3% (95% CI; 49.0%, 67.2%) of ipilimumab alone (two-sided P=.04). Conclusion and Relevance Among patients with unresectable stage III or IV melanoma, treatment with sargramostim plus ipilimumab, compared to ipilimumab alone, resulted in longer overall survival and lower toxicity, but no difference in progression free survival. These findings require confirmation in larger sample sizes and longer follow up.

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MFG-E8–mediated uptake of apoptotic cells by APCs links the pro- and antiinflammatory activities of GM-CSF

Cited by 183 publications

References 47 publications

The inhibition of the T-cell immunoglobulin and mucin domain 3 (Tim3) pathway enhances the efficacy of tumor vaccine

The inhibition of the T-cell immunoglobulin and mucin domain 3 (Tim3) pathway enhances the efficacy of tumor vaccine

Milk fat globule—epidermal growth factor—factor VIII (MFGE8)/lactadherin promotes bladder tumor development

Ipilimumab Plus Sargramostim vs Ipilimumab Alone for Treatment of Metastatic Melanoma

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