Single-cell RNA-seq of a soft-tissue sarcoma model reveals the critical role of tumor-expressed MIF in shaping macrophage heterogeneity

Tessaro, Fernando Henrique Galvão; Ko, Emily Y.; Simone, Marco De; Piras, Roberta; Broz, Marina T; Goodridge, Helen S.; Balzer, Bonnie; Shiao, Stephen L.; Guarnerio, Jlenia

doi:10.1016/j.celrep.2022.110977

Cited by 22 publications

(18 citation statements)

References 40 publications

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“…7C). MIF expression, as well as the receptors CD74 and CXCR4, are highly expressed in this cell type and as mentioned above, can promote a pro-tumor TME 75, 76 . We also identified that several T cell subtypes express the receptor CD161 (encoded by KLRB1) and the ligands, LLT1 (encoded by CLEC2D) and CD69 (also known as CLEC2C) (Fig.…”

Section: Resultsmentioning

confidence: 76%

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Characterization of transcriptional heterogeneity and novel therapeutic targets using single cell RNA-sequencing of primary and circulating Ewing sarcoma cells

Goodspeed,

Bodlak,

Duffy

et al. 2024

Preprint

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Ewing sarcoma is the second most common bone cancer in children, accounting for 2% of pediatric cancer diagnoses. Patients who present with metastatic disease at the time of diagnosis have a dismal prognosis, compared to the >70% 5-year survival of those with localized disease. Here, we utilized single cell RNA-sequencing to characterize the transcriptional landscape of primary Ewing sarcoma tumors and surrounding tumor microenvironment (TME). Copy-number analysis identified subclonal evolution within patients even prior to treatment. Primary tumor samples demonstrate a heterogenous transcriptional landscape with several conserved gene expression programs, including those composed of genes related to proliferation and EWS targets. We also were able to identify the composition of the TME and molecularly dissect the transcriptional profile of circulating tumor cells in peripheral blood at the time of diagnosis.

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Section: Resultsmentioning

confidence: 76%

“…MIF was originally discovered as a cytokine that regulates inflammation and immune activation, and is known to bind to the CD74/CD44 complex 73 , CXCR2 and CXCR4 74 . In mouse models of soft tissue sarcoma and melanoma, MIF has been reported to interact with CD74 expressing myeloid cells in the TME causing remodeling to a pro-tumor TME 75, 76 .…”

Section: Resultsmentioning

confidence: 99%

Characterization of transcriptional heterogeneity and novel therapeutic targets using single cell RNA-sequencing of primary and circulating Ewing sarcoma cells

Goodspeed,

Bodlak,

Duffy

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Furthermore, the number of macrophages positively correlated with histologic grade of the tumor and with the number of mitoses found in the tissue, suggesting macrophages to be an important feature driving tumor grade. Similarly, CD74-positive macrophages have been found to promote tumor growth in a mouse model of undifferentiated pleomorphic sarcoma [49] . In human STS, UPS and Myxofibrosarcomas were found to have the highest median macrophage score of all sarcoma types [50] , and a high number of CD68 + macrophages are discussed as negative prognostic factors for a series of STS, including Osteosarcoma and Ewing Sarcoma (reviewed in [51] ).…”

Section: Discussionmentioning

confidence: 91%

Proteomic profiling of canine fibrosarcoma and adjacent peritumoral tissue

et al. 2023

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“…This has also been described in other malignancies. In soft-tissue sarcoma, tumor-secreted MIF can shape macrophages to become more pro-tumorigenic and in melanoma, MIF has been described to tune myeloid-derived suppressor cells to hinder cytotoxicity of T cells 74,75 . In rhabdomyosarcoma, MIF knock-out increased the potential of cellular immune interventions 76 .…”

Section: Discussionmentioning

confidence: 99%

Blocking MIF secretion enhances CAR T-cell efficacy against neuroblastoma

Strijker,

Pascual-Pasto,

Kalmeijer

et al. 2024

Preprint

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While chimeric antigen receptor (CAR) T-cell therapies are showing highly promising first results in neuroblastoma, immunosuppressive tumor microenvironments (TME) limit T cell persistence and durable clinical efficacy. To improve CAR T-cell efficacy further, we applied a multi-omics approach including single-cell RNA sequencing and proteomics, which identified 13 targetable immunosuppressive factors in neuroblastoma. Of these, macrophage migration inhibitory factor (MIF) and midkine (MDK) were validated across multiple published RNA datasets. Moreover, they were secreted in high abundance by neuroblastoma tumoroids. Functional validation experiments revealed MIF as a potent inhibitor of CAR T-cells,in vitroandin vivo.Degradation of MIF by PROTAC technology significantly enhanced CAR T-cell activation targeting GPC2 and B7-H3, providing a potential intervention against MIF. By defining the immunosuppressive effects of neuroblastoma’s TME on CAR T-cell efficacy, particularly the pivotal role of MIF, we provide a therapeutic strategy for improving adoptive cell therapies for this pediatric malignancy.

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Single-cell RNA-seq of a soft-tissue sarcoma model reveals the critical role of tumor-expressed MIF in shaping macrophage heterogeneity

Cited by 22 publications

References 40 publications

Characterization of transcriptional heterogeneity and novel therapeutic targets using single cell RNA-sequencing of primary and circulating Ewing sarcoma cells

Characterization of transcriptional heterogeneity and novel therapeutic targets using single cell RNA-sequencing of primary and circulating Ewing sarcoma cells

Proteomic profiling of canine fibrosarcoma and adjacent peritumoral tissue

Blocking MIF secretion enhances CAR T-cell efficacy against neuroblastoma

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