Targeted delivery of zoledronic acid through the sialic acid - Siglec axis for killing and reversal of M2 phenotypic tumor-associated macrophages – A promising cancer immunotherapy

Tang, Xueying; Sui, Dezhi; Liu, Mingqi; Zhang, Hongxia; Liu, Min; Wang, Suo; Zhao, Dan; Sun, Wenliang; Li, Mengyang; Luo, Xiang; Lai, Xiaoxue; Liu, Xinrong; Deng, Yihui; Song, Yanzhi

doi:10.1016/j.ijpharm.2020.119929

Cited by 32 publications

(19 citation statements)

References 42 publications

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“…Siglec members can recognize sialoglycans on immune cells or tumor cells to cause stimulatory or inhibitory effects (24). Siglec-15, first reported in 2001, is a new member of Siglecs and has been involved in many tumors' development (19,25,26).…”

Section: Discussionmentioning

confidence: 99%

Siglec-15 Promotes Tumor Progression in Osteosarcoma via DUSP1/MAPK Pathway

et al. 2021

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Recurrence and metastasis are important features of osteosarcoma (OS) that cause its poor prognosis. Aberrant expression of Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) has been reported in various kinds of cancers. However, the expression and function of Siglec-15 in OS remain unclear. In cultured OS cells (143B cells and MNNG/HOS cells) and their xenograft mouse models, we found that downregulation of Siglec-15 could inhibit the proliferation, migration and invasion of by inducing epithelial-mesenchymal transition (EMT) in vitro and in vivo. Conversely, Siglec-15 overexpression promoted the growth, migration and invasion of OS cells in a significant manner. Then, we screened a number of differentially expressed genes (DEGs) between Siglec-15-knockdown group and control group by RNA-Seq assay. Among these DEGs, we found that dual-specificity phosphatase 1 (DUSP1/MKP1) was significantly downregulated after Siglec-15 silencing. We investigated the DUSP1 functions in influencing OS cells’ biology, and found that the proliferation, migration and invasion of OS cells were promoted by overexpressing DUSP1 and crucially, the proliferation, migration and invasion of Siglec-15-knockdown OS cells were rescued by overexpressing DUSP1. Mechanically, we further showed that DUSP1-mediated inhibition of p38/MAPK and JNK/MAPK expression was attenuated when Siglec-15 expression was inhibited, suggesting that Siglec-15 promotes the malignant progression of OS cells by suppressing DUSP1-mediated suppression of the MAPK pathway. Moreover, we showed that both Siglec-15 and DUSP1 were highly expressed in human OS tissues by immunohistochemistry. High Siglec-15 expression was associated with OS lung metastasis, and high DUSP1 expression was associated with the high Enneking stage. Kaplan–Meier analysis indicated that high expression of Siglec-15 could predict poor prognosis of OS patients. Altogether, these results showed that Siglec-15 expression promoted OS development and progression by activating DUSP1 and might be a novel target in OS treatment.

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Section: Discussionmentioning

confidence: 99%

Siglec-15 Promotes Tumor Progression in Osteosarcoma via DUSP1/MAPK Pathway

et al. 2021

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“…Liposome-encapsulated bisphosphonates (e.g., zoledronic acid-or clodroenate-loaded liposomes) have been widely applied for the depletion of TAMs in murine tumor models, resulting in markedly reduced tumor growth and metastasis. 596,597 Furthermore, treatment with bisphosphonates or their combination with other antitumor therapies markedly reduced the recurrence and overall mortality of breast and prostate cancer. 595,598 As the first marine-derived anti-tumor agent approved for the treatment of soft tissue sarcoma and OVC, trabectedin was also found to suppress the accumulation of macrophages in TME and the production of inflammatory mediators from TAMs, such as IL-6, CCL2, CXCL8, angiopoietin 2, and VEGF.…”

Section: Adjusting the Inflammation In Innate Immunitymentioning

confidence: 99%

Inflammation and tumor progression: signaling pathways and targeted intervention

Zhao

Yan

et al. 2021

Sig Transduct Target Ther

1,265

682

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Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses tumor progression, potentially displaying opposing effects on therapeutic outcomes. Chronic inflammation facilitates tumor progression and treatment resistance, whereas induction of acute inflammatory reactions often stimulates the maturation of dendritic cells (DCs) and antigen presentation, leading to anti-tumor immune responses. In addition, multiple signaling pathways, such as nuclear factor kappa B (NF-kB), Janus kinase/signal transducers and activators of transcription (JAK-STAT), toll-like receptor (TLR) pathways, cGAS/STING, and mitogen-activated protein kinase (MAPK); inflammatory factors, including cytokines (e.g., interleukin (IL), interferon (IFN), and tumor necrosis factor (TNF)-α), chemokines (e.g., C-C motif chemokine ligands (CCLs) and C-X-C motif chemokine ligands (CXCLs)), growth factors (e.g., vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β), and inflammasome; as well as inflammatory metabolites including prostaglandins, leukotrienes, thromboxane, and specialized proresolving mediators (SPM), have been identified as pivotal regulators of the initiation and resolution of inflammation. Nowadays, local irradiation, recombinant cytokines, neutralizing antibodies, small-molecule inhibitors, DC vaccines, oncolytic viruses, TLR agonists, and SPM have been developed to specifically modulate inflammation in cancer therapy, with some of these factors already undergoing clinical trials. Herein, we discuss the initiation and resolution of inflammation, the crosstalk between tumor development and inflammatory processes. We also highlight potential targets for harnessing inflammation in the treatment of cancer.

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“…TAM is a promising therapeutic target for cancer therapy 40 , 41 . TAM as a vaccination target providies the unique advantages over cancer cells, in terms of the less mutation frequency and genetic variation.…”

Section: Discussionmentioning

confidence: 99%

Genetically-engineered “all-in-one” vaccine platform for cancer immunotherapy

Chen

Wang

et al. 2021

Acta Pharmaceutica Sinica B

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An essential step for cancer vaccination is to break the immunosuppression and elicit a tumor-specific immunity. A major hurdle against cancer therapeutic vaccination is the insufficient immune stimulation of the cancer vaccines and lack of a safe and efficient adjuvant for human use. We discovered a novel cancer immunostimulant, trichosanthin (TCS), that is a clinically used protein drug in China, and developed a well-adaptable protein-engineering method for making recombinant protein vaccines by fusion of an antigenic peptide, TCS, and a cell-penetrating peptide (CPP), termed an “all-in-one” vaccine, for transcutaneous cancer immunization. The TCS adjuvant effect on antigen presentation was investigated and the antitumor immunity of the vaccines was investigated using the different tumor models. The vaccines were prepared via a facile recombinant method. The vaccines induced the maturation of DCs that subsequently primed CD8 + T cells. The TCS-based immunostimulation was associated with the STING pathway. The general applicability of this genetic engineering strategy was demonstrated with various tumor antigens ( i.e. , legumain and TRP2 antigenic peptides) and tumor models ( i.e. , colon tumor and melanoma). These findings represent a useful protocol for developing cancer vaccines at low cost and time-saving, and demonstrates the adjuvant application of TCS—an old drug for a new application.

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Targeted delivery of zoledronic acid through the sialic acid - Siglec axis for killing and reversal of M2 phenotypic tumor-associated macrophages – A promising cancer immunotherapy

Cited by 32 publications

References 42 publications

Siglec-15 Promotes Tumor Progression in Osteosarcoma via DUSP1/MAPK Pathway

Siglec-15 Promotes Tumor Progression in Osteosarcoma via DUSP1/MAPK Pathway

Inflammation and tumor progression: signaling pathways and targeted intervention

Genetically-engineered “all-in-one” vaccine platform for cancer immunotherapy

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