Targeting the Tumor Microenvironment in Neuroblastoma: Recent Advances and Future Directions

Joshi, Shweta

doi:10.3390/cancers12082057

Cited by 59 publications

(43 citation statements)

References 205 publications

(261 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…39 Targeting the TME along with tumor cells has been reported beneficial to a subgroup of high-risk NB patients. 40 As one of the major components belonging to the innate immune system, reactivating TAMs is necessary for reversing immune suppressive state and stimulating immune defense to exert tumoricidal function. Our data revealed that CD209 + CD36 + TAMs were more existed in the advanced stage of NB, while CD80 + CCR7 + TAMs as well as CD14 + CD16classic monocytes were more existed in tissues and PBMCs of early-stage NB, indicating the tumor-inhibiting and tumor-promoting TME in early and advanced NB environment, respectively.…”

Section: Discussionmentioning

confidence: 99%

FABP4 deactivates NF‐κB‐IL1α pathway by ubiquitinating ATPB in tumor‐associated macrophages and promotes neuroblastoma progression

Miao

Zhang

Tang

et al. 2021

Clinical & Translational Med

View full text Add to dashboard Cite

Neuroblastoma (NB) is the most common and deadliest pediatric solid tumor. Targeting and reactivating tumor‐associated macrophages (TAMs) is necessary for reversing immune suppressive state and stimulating immune defense to exert tumoricidal function. However, studies on the function and regulation of TAMs in NB progression are still limited. Fatty acid binding protein 4 (FABP4) in TAMs was correlated with advanced clinical stages and unfavorable histology of NB. FABP4‐mediated macrophages increased migration, invasion, and tumor growth of NB cells. Mechanically, FABP4 could directly bind to ATPB to accelerate ATPB ubiquitination in macrophages. The consequently decreased ATP levels could deactivate NF‐κB/RelA‐IL1α pathway, which subsequently results in macrophages reprogrammed to an anti‐inflammatory phenotype. We also demonstrated that FABP4‐enhanced migration and invasion were significantly suppressed by IL1α blocking antibody. Furthermore, circulating FABP4 was also associated with the clinical stages of NB. Our findings suggest that FABP4‐mediated macrophages may promote proliferation and migration phenotypes in NB cells through deactivating NF‐κB‐IL1α pathway by ubiquitinating ATPB. This study reveals the pathologic and biologic role of FABP4‐mediated macrophages in NB development and exhibits a novel application of targeting FABP4 in macrophages for NB treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

FABP4 deactivates NF‐κB‐IL1α pathway by ubiquitinating ATPB in tumor‐associated macrophages and promotes neuroblastoma progression

Miao

Zhang

Tang

et al. 2021

Clinical & Translational Med

View full text Add to dashboard Cite

show abstract

“…Survival varies from nearly 100% for low-risk patients to less than 40% in the high-risk group. Their current treatment combines surgery, chemotherapy, radiation, and immunotherapy [ 104 ].…”

Section: Antiangiogenics and Neuroblastomamentioning

confidence: 99%

“…High-risk neuroblastomas are characterized by being very aggressive and have a highly vascular, angiogenic, hypoxic, and immunosuppressive TME [ 104 , 105 , 106 ]. They also express large amounts of VEGF, PlGF, FGF, PDGF, and endoglin [ 104 , 107 , 108 , 109 , 110 , 111 ], so some antiangiogenics against these targets have been used in patients and preclinical models of neuroblastoma.…”

Section: Antiangiogenics and Neuroblastomamentioning

confidence: 99%

Use of Antiangiogenic Therapies in Pediatric Solid Tumors

Ollauri-Ibáñez

Astigarraga

2021

Cancers

View full text Add to dashboard Cite

Cancer is an important cause of death in childhood. In recent years, scientists have made an important effort to achieve greater precision and more personalized treatments against cancer. But since only a few pediatric patients have identifiable therapeutic targets, other ways to stop the neoplastic cell proliferation and dissemination are needed. Therefore, the inhibition of general processes involved in the growth and behavior of tumors can be a relevant strategy for the development of new cancer therapies. In the case of solid tumors, one of these processes is angiogenesis, essential for tumor growth and generation of metastases. This review summarizes the results obtained with the use of antiangiogenic drugs in the main pediatric malignant solid tumors and also an overview of clinical trials currently underway. It should be noted that due to the rarity and heterogeneity of the different types of pediatric cancer, most studies on antiangiogenic drugs include only a small number of patients or isolated clinical cases, so they are not conclusive and further studies are needed.

show abstract

“…These extracranial tumors commonly arise in and around the adrenal glands and are rare in kids older than 10 years of age [1,2] The amplification of MYCN oncogene is frequently observed in NB tumors and despite intensive multimodal treatments, which include chemotherapy, radiotherapy, anti-GD2 immunotherapy, and stem cell transplant, the overall survival of patients diagnosed with high-risk disease is less than 50%. The infiltration and accumulation of immunosuppressive myeloid cells, specifically myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) in NB tumors, diminish effective antitumor immune responses, which leads to failure of immunotherapy and other conventional therapies in this childhood cancer [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

BTK Inhibition Reverses MDSC-Mediated Immunosuppression and Enhances Response to Anti-PDL1 Therapy in Neuroblastoma

Ishfaq

Pham

Beaman

et al. 2021

Cancers

Self Cite

View full text Add to dashboard Cite

MDSCs are immune cells of myeloid lineage that plays a key role in promoting tumor growth. The expansion of MDSCs in tumor-bearing hosts reduces the efficacy of checkpoint inhibitors and CAR-T therapies, and hence strategies that deplete or block the recruitment of MDSCs have shown benefit in improving responses to immunotherapy in various cancers, including NB. Ibrutinib, an irreversible molecular inhibitor of BTK, has been widely studied in B cell malignancies, and recently, this drug is repurposed for the treatment of solid tumors. Herein we report that BTK is highly expressed in both granulocytic and monocytic murine MDSCs isolated from mice bearing NB tumors, and its increased expression correlates with a poor relapse-free survival probability of NB patients. Moreover, in vitro treatment of murine MDSCs with ibrutinib altered NO production, decreased mRNA expression of Ido, Arg, Tgfβ, and displayed defects in T-cell suppression. Consistent with these findings, in vivo inhibition of BTK with ibrutinib resulted in reduced MDSC-mediated immune suppression, increased CD8+ T cell infiltration, decreased tumor growth, and improved response to anti-PDL1 checkpoint inhibitor therapy in a murine model of NB. These results demonstrate that ibrutinib modulates immunosuppressive functions of MDSC and can be used either alone or in combination with immunotherapy for augmenting antitumor immune responses in NB.

show abstract

Targeting the Tumor Microenvironment in Neuroblastoma: Recent Advances and Future Directions

Cited by 59 publications

References 205 publications

FABP4 deactivates NF‐κB‐IL1α pathway by ubiquitinating ATPB in tumor‐associated macrophages and promotes neuroblastoma progression

FABP4 deactivates NF‐κB‐IL1α pathway by ubiquitinating ATPB in tumor‐associated macrophages and promotes neuroblastoma progression

Use of Antiangiogenic Therapies in Pediatric Solid Tumors

BTK Inhibition Reverses MDSC-Mediated Immunosuppression and Enhances Response to Anti-PDL1 Therapy in Neuroblastoma

Contact Info

Product

Resources

About