The Macrophage Inhibitor CNI-1493 Blocks Metastasis in a Mouse Model of Ewing Sarcoma through Inhibition of Extravasation

Hesketh, Anthony J.; Maloney, Caroline; Behr, Christopher A.; Edelman, Morris; Glick, Richard D.; Al‐Abed, Yousef; Symons, Marc; Soffer, Samuel Z.; Steinberg, Bettie M.

doi:10.1371/journal.pone.0145197

Cited by 16 publications

(20 citation statements)

References 75 publications

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“…prognostic marker in some sarcomas, and macrophage blockade in sarcoma xenograft models has led to improved disease control. [40][41][42][43][44][45] Since macrophages may play a role in immunemediated resistance in sarcomas, further investigations into targeting both PD-L1 and macrophages are warranted.…”

Section: Discussionmentioning

confidence: 99%

Osteosarcoma and soft-tissue sarcomas with an immune infiltrate express PD-L1: relation to clinical outcome and Th1 pathway activation

et al. 2020

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Immune checkpoint proteins, such as PD-L1 and PD-1, are important in several cancers; however, their role in osteosarcoma (OSA) and soft tissue sarcoma (STS) remains unclear. Our aims were to determine whether subsets of OSA/STS harbor tumor-infiltrating lymphocytes (TILs) and express PD-L1, and how PD-L1 expression is related to clinical outcome. Tissue sections of 25 cases each of untreated undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), liposarcoma (LPS) and 24 of leiomyosarcoma (LMS) were subjected to immunohistochemistry (IHC) for immune cells, PD-L1 and PD-1. RT-qPCR was utilized to quantify levels of PD-L1 mRNA from 33 UPS, 57 MFS and 79 OSA primary-untreated specimens. PD-L1 mRNA levels were tested for their correlation with overall survival in patients presenting without metastases. Transcriptome analysis evaluated biological pathway differences between high and low PD-L1 expressers. A subset of UPS and MFS contained TILs and expressed PD-L1 and PD-1; LMS and LPS did not. PD-L1 levels by IHC and RT-qPCR were positively correlated. PD-L1 over-expression was associated with better survival for UPS and OSA, but not MFS. The Th1 pathway was significantly activated in UPS with high levels of PD-L1 and improved survival. Some sarcoma subtypes harbor TILs and express PD-L1. Patients with UPS and OSA with high levels of PD-L1 had better overall survival than those with low expression levels. Important biological pathways distinguish PD-L1 high and low groups. The stratification of patients with OSA/STS with respect to potential immune therapies may be improved through investigation of the expression of immune cells and checkpoint proteins.

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Section: Discussionmentioning

confidence: 99%

Osteosarcoma and soft-tissue sarcomas with an immune infiltrate express PD-L1: relation to clinical outcome and Th1 pathway activation

et al. 2020

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“…Recently, Saos-2 osteosarcoma cells (1 × 10 6 cells/mouse) were injected intraperitoneally in nude mice, resulting in the induction of osteosarcoma xenograft models [27] . SK-NEP-1 Ewing sarcoma cells were inoculated under the renal capsule of mice, this model displaying the advantage of reproducing the lung metastatic spreading after the inoculation of 1 × 10 6 cells [28] . Ewing sarcoma tumours were formed after injection of 2 × 10 6 TC71 Ewing Sarcoma cells into the gastrocnemius muscle [29] .…”

Section: Induction Of Primary Bone Tumour By Cell Injections In Hetermentioning

confidence: 99%

Small animal models for the study of bone sarcoma pathogenesis:characteristics, therapeutic interests and limitations

Jacques

Renema

Lezot

et al. 2018

Journal of Bone Oncology

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Osteosarcoma, Ewing sarcoma and chondrosarcoma are the three main entities of bone sarcoma which collectively encompass more than 50 heterogeneous entities of rare malignancies. In contrast to osteosarcoma and Ewing sarcoma which mainly affect adolescents and young adults and exhibit a high propensity to metastasise to the lungs, chondrosarcoma is more frequently observed after 40 years of age and is characterised by a high frequency of local recurrence. The combination of chemotherapy, surgical resection and radiotherapy has contributed to an improved outcome for these patients. However, a large number of patients still suffer significant therapy related toxicities or die of refractory and metastatic disease. To better delineate the pathogenesis of bone sarcomas and to identify and test new therapeutic options, major efforts have been invested over the past decades in the development of relevant pre-clinical animal models. Nowadays, in vivo models aspire to mimic all the steps and the clinical features of the human disease as accurately as possible and should ideally be manipulable. Considering these features and given their small size, their conduciveness to experiments, their affordability as well as their human-like bone-microenvironment and immunity, murine pre-clinical models are interesting in the context of these pathologies. This chapter will provide an overview of the murine models of bone sarcomas, paying specific attention for the models induced by inoculation of tumour cells. The genetically-engineered mouse models of bone sarcoma will also be summarized.

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“…A recent study using resveratrol, a compound that indirectly inhibits pro-tumor macrophage (M2) activation, indicated it had anti-metastatic effects [ 111 ]. Similarly, the selective TAM inhibitor CNI-1493, which inhibits the production of macrophage-derived inflammatory mediators, also demonstrated an anti-metastatic effect through the inhibition of cancer cell extravasation [ 112 ]. Thus, the inhibition of macrophages could have clinical anti-metastatic potential.…”

Section: Introductionmentioning

confidence: 99%

The immune system in cancer metastasis: friend or foe?

Janssen

Ramsay

Logsdon

et al. 2017

j. immunotherapy cancer

234

183

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Metastatic disease is the leading cause of death among cancer patients and involves a complex and inefficient process. Every step of the metastatic process can be rate limiting and is influenced by non-malignant host cells interacting with the tumor cell. Over a century ago, experiments first indicated a link between the immune system and metastasis. This phenomenon, called concomitant immunity, indicates that the primary tumor induces an immune response, which may not be sufficient to destroy the primary tumor, but prevents the growth of a secondary tumor or metastases. Since that time, many different immune cells have been shown to play a role in both inhibiting and promoting metastatic disease. Here we review classic and new observations, describing the links between the immune system and metastasis that inform the development of cancer therapies.

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The Macrophage Inhibitor CNI-1493 Blocks Metastasis in a Mouse Model of Ewing Sarcoma through Inhibition of Extravasation

Cited by 16 publications

References 75 publications

Osteosarcoma and soft-tissue sarcomas with an immune infiltrate express PD-L1: relation to clinical outcome and Th1 pathway activation

Osteosarcoma and soft-tissue sarcomas with an immune infiltrate express PD-L1: relation to clinical outcome and Th1 pathway activation

Small animal models for the study of bone sarcoma pathogenesis:characteristics, therapeutic interests and limitations

The immune system in cancer metastasis: friend or foe?

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