A paracrine circuit of IL-1β/IL-1R1 between myeloid and tumor cells drives glioblastoma progression

Chen, Zhihong; Giotti, Bruno; Kaluzová, Milota; Herting, Cameron J.; Piñero, Gonzalo; Vallcorba, Montserrat Puigdelloses; Cristea, Simona; Ackley, James C.; Maximov, Victor; Szulzewsky, Frank; Marquez-Ropero, Mar; Angione, Angelo; Nichols, Noah; Tsankkova, Nadejda; Michor, Franziska; Shayakhmetov, Dmitry M.; Gutmann, David H.; Tsankov, Alexander M.; Hambardzumyan, Dolores

doi:10.1101/2022.04.03.486888

Cited by 8 publications

(9 citation statements)

References 53 publications

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“…While T cell-activating immunotherapies, such as anti-PD1, led to remarkable responses in brain metastases (6), the outcomes in the treatment of primary brain tumors, such as glioblastoma (GBM), were disappointing (7,8). Although the reason for these poor outcomes remains elusive, increasing evidence suggests that more effective targeting of the immune cells in the tumor microenvironment (TME) may lead to improved outcomes (9)(10)(11)(12). In addition, intensive treatment protocols based on multiple and frequent dosing have shown improved outcomes (10), supporting the notion that improved local delivery can be beneficial.…”

Section: Introductionmentioning

confidence: 99%

Spatially targeted brain cancer immunotherapy with closed-loop controlled focused ultrasound and immune checkpoint blockade

et al. 2022

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Despite the challenges in treating glioblastomas (GBMs) with immune adjuvants, increasing evidence suggests that targeting the immune cells within the tumor microenvironment (TME) can lead to improved responses. Here, we present a closed-loop controlled, microbubble-enhanced focused ultrasound (MB-FUS) system and test its abilities to safely and effectively treat GBMs using immune checkpoint blockade. The proposed system can fine-tune the exposure settings to promote MB acoustic emission–dependent expression of the proinflammatory marker ICAM-1 and delivery of anti-PD1 in a mouse model of GBM. In addition to enhanced interaction of proinflammatory macrophages within the PD1-expressing TME and significant improvement in survival ( P < 0.05), the combined treatment induced long-lived memory T cell formation within the brain that supported tumor rejection in rechallenge experiments. Collectively, our findings demonstrate the ability of MB-FUS to augment the therapeutic impact of immune checkpoint blockade in GBMs and reinforce the notion of spatially tumor-targeted (loco-regional) brain cancer immunotherapy.

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Section: Introductionmentioning

confidence: 99%

Spatially targeted brain cancer immunotherapy with closed-loop controlled focused ultrasound and immune checkpoint blockade

et al. 2022

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“…However, we didn’t find any specific records for gliomas, lung or kidney cancers. Still, several preclinical investigations have shown that targeting of IL1 signaling in GBM ( 137 , 138 ), LGG ( 139 ) kidney ( 140 ) and lung cancer ( 141 ) suggest its potential clinical usefulness.…”

Section: Molecules Involved In the Ctc Heterotypic Interaction And Kn...mentioning

confidence: 99%

Molecules promoting circulating clusters of cancer cells suggest novel therapeutic targets for treatment of metastatic cancers

Rozenberg

Buzdin²,

Mohammad³

et al. 2023

Front. Immunol.

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Treatment of metastatic disease remains among the most challenging tasks in oncology. One of the early events that predicts a poor prognosis and precedes the development of metastasis is the occurrence of clusters of cancer cells in the blood flow. Moreover, the presence of heterogeneous clusters of cancerous and noncancerous cells in the circulation is even more dangerous. Review of pathological mechanisms and biological molecules directly involved in the formation and pathogenesis of the heterotypic circulating tumor cell (CTC) clusters revealed their common properties, which include increased adhesiveness, combined epithelial-mesenchymal phenotype, CTC-white blood cell interaction, and polyploidy. Several molecules involved in the heterotypic CTC interactions and their metastatic properties, including IL6R, CXCR4 and EPCAM, are targets of approved or experimental anticancer drugs. Accordingly, analysis of patient survival data from the published literature and public datasets revealed that the expression of several molecules affecting the formation of CTC clusters predicts patient survival in multiple cancer types. Thus, targeting of molecules involved in CTC heterotypic interactions might be a valuable strategy for the treatment of metastatic cancers.

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“…COL5A1 was described as biomarker of poor prognosis, promoting glioblastoma progression via the PPRC1-ESM1 axis, and a mesenchymal-subtype-related gene [30][31][32]. IL1R1 was shown to be linked with brain edema and tumor progression in mice [33,34]. While IL7R was not described as associated with glioblastoma pathogenesis or molecular subtype, there are 51 PubMed articles linking PLAUR and glioblastoma (https://pubmed.ncbi.nlm.nih.gov/?term=plaur+glioblastoma, date of access 28 May 2022).…”

Section: Gene Biomarkersmentioning

confidence: 99%

Next-Generation Grade and Survival Expression Biomarkers of Human Gliomas Based on Algorithmically Reconstructed Molecular Pathways

Zolotovskaia

Kovalenko

Tkachev³

et al. 2022

IJMS

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In gliomas, expression of certain marker genes is strongly associated with survival and tumor type and often exceeds histological assessments. Using a human interactome model, we algorithmically reconstructed 7494 new-type molecular pathways that are centered each on an individual protein. Each single-gene expression and gene-centric pathway activation was tested as a survival and tumor grade biomarker in gliomas and their diagnostic subgroups (IDH mutant or wild type, IDH mutant with 1p/19q co-deletion, MGMT promoter methylated or unmethylated), including the three major molecular subtypes of glioblastoma (proneural, mesenchymal, classical). We used three datasets from The Cancer Genome Atlas and the Chinese Glioma Genome Atlas, which in total include 527 glioblastoma and 1097 low grade glioma profiles. We identified 2724 such gene and 2418 pathway survival biomarkers out of total 17,717 genes and 7494 pathways analyzed. We then assessed tumor grade and molecular subtype biomarkers and with the threshold of AUC > 0.7 identified 1322/982 gene biomarkers and 472/537 pathway biomarkers. This suggests roughly two times greater efficacy of the reconstructed pathway approach compared to gene biomarkers. Thus, we conclude that activation levels of algorithmically reconstructed gene-centric pathways are a potent class of new-generation diagnostic and prognostic biomarkers for gliomas.

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A paracrine circuit of IL-1β/IL-1R1 between myeloid and tumor cells drives glioblastoma progression

Cited by 8 publications

References 53 publications

Spatially targeted brain cancer immunotherapy with closed-loop controlled focused ultrasound and immune checkpoint blockade

Spatially targeted brain cancer immunotherapy with closed-loop controlled focused ultrasound and immune checkpoint blockade

Molecules promoting circulating clusters of cancer cells suggest novel therapeutic targets for treatment of metastatic cancers

Next-Generation Grade and Survival Expression Biomarkers of Human Gliomas Based on Algorithmically Reconstructed Molecular Pathways

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