國家衛生研究院 NHRI:Item 3990099045/16101

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Title:	Multimodal analysis of glioblastoma reveals the potential of cxcr7-cxcl12 in gbm cells sensitizes gbm to immune checkpoint blockade therapy
Authors:	Liu, C;Chien, C;Yang, W;Chuang, J;Chang, K
Contributors:	National Institute of Cancer Research
Abstract:	BACKGROUND: Glioblastoma (GBM), a WHO Grade IV glioma, is one of the most lethal brain tumors. In spite of the standard of care and currently developed advanced treatment, the prognosis of GBM patients is still poor. In addition to the understanding of GBM cells, the microenvironment plays a critical role in regulating GBM progression. Also, more and more information indicates the interaction of GBM-associated macrophages (GAMs) and GBM cells facilitates GBM progression via sculpturing immunosurveillance, cancer stemness, and cancer resistance. And thus, we hypothesized that GBM cells sculptured the microenvironment via macrophage alternation of which interventions may potentialize immune checkpoint blockade therapy. MATERIAL AND METHODS: The bulk RNA sequencing (seq.) of the paired primary-recurrent GBM specimens, single-cell RNA seq., in vitro (including mRNA, protein, and cell behavior tests), and in vivo validation, were integrated to explore our hypothesis. RESULTS: The bulk RNA seq. of the paired primary-recurrent GBM specimens showed recurrent GBM enhanced the neuroinflammation pathway. Among the secretory components, CXCL12, also known as stromal cell-derived factor 1 was accumulated during GBM progression and upregulated in temozolomide (TMZ)-resistant GBM cells compared with parental GBM cell lines. In addition, the newly CXCL12 receptor CXCR7 may act as a scavenger to breakdown CXCL12-CXCR4 positive feedback in GBM resistance. Moreover, the bulk RNA sequencing seq. showed that recurrent GBM reduced CXCR7 expression. Single-cell RNA seq. of GBM patients’ specimens suggested that CXCR7 was majorly expressed in GBM cells than in normal neural and immune cells. Developing TMZ resistance in GBM cell lines also down-regulated CXCR7 expression. Furthermore, silencing CXCR7 attenuated TMZ cytotoxicity while silencing CXCR7 and CXCL12 simultaneously reversed the effects. In contrast, combining CXCR7 agonists and TMZ enhanced TMZ cytotoxicity Otherwise, the GBM-associated CXCL12 activated M0 macrophages into GAMs by facilitating macrophage proliferation and inducing pro-tumor factors, including IL-1β and its receptors, IL-6, MMP9, and immune checkpoint PD-L1. Mechanistically, GBM-associated CXCL12 upregulated PD-L1 in GAMs via NF-κB. Also, in the orthotopic GBM mouse model, CXCR7 knockdown in GBM cells led to poor survival and increased PD-L1 expression in GAMs. Finally, we combined CXCR7 agonist and anti-PD-L1 to show prolonged survival, in contrast, anti-PD-L1 did not show this effect. CONCLUSION: In accordance with the multimodal analysis, GBM regulated the accumulation of CXCL12 via silencing CXCR7 in GBM cells. The CXCR7-CXCL12 axis confers the immunosuppression by up-regulating PD-L1 in GAMs. Our study suggested that CXCR7 activation treatment alone or combined with an immune checkpoint inhibitor may be a potential strategy for the treatment of GBM.
Date:	2023-09-08
Relation:	Neuro-Oncology. 2023 Sep 08;25(Suppl. 2):ii96-ii97.
Link to:	http://dx.doi.org/10.1093/neuonc/noad137.322
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1522-8517&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:001300535600323
Appears in Collections:	[Kwang-Yu Chang] Conference Papers/Meeting Abstract

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