P0288 : CXCR4 inhibition reverts immunosuppressive tumor microenvironment and facilitates Anti-PD-1 immunotherapy in sorafenib-treated hepatocellular carcinoma

Reiberger, T; Yunching, C.; Ramjiawan, Rakesh R.; Ng, Rainov; Hato, Tai; Huang, Yuanyi; Unan, Elizabeth C.; Reddy, Tejaswini P.; Fan, Chuanfeng; Huang, Peigen; Bardeesy, Nabeel; Jain, RK; Duda, Dan G.

doi:10.1016/s0168-8278(15)30504-3

Cited by 2 publications

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“…Most recently, many studies have focused on the role of immunosuppression in sorafenib resistance. Immunosuppression-related resistance to sorafenib has been attributed to hypoxia, demonstrated by the upregulated expression of immune checkpoint inhibitor programmed death ligand-1 (PD-L1) (25) and increased infiltration of Gr1 + myeloid-derived suppressive cells, regulatory T cells, M2 macrophages (26), and tumor-associated neutrophils (27), which may be associated with increased SDF1α, CXCR4, CCL2/CCR2, and CCL17 expression levels in tumors (25)(26)(27)(28)(29). Modulation of immune responses by combining a CCR2 antagonist with a CXCR4 inhibitor and an anti-PD-1 antibody synergized sorafenib effects through elevated intratumoral infiltration of CD8+ T cells, and increased expression levels of IL-2, TNF-α, and interferon gamma (IFN-γ) (25,26,28,30).…”

Section: Discussionmentioning

confidence: 99%

Underlying mechanism of sorafenib resistance in hepatocellular carcinoma: a bioinformatics study based on validated resistance-related genes

Song¹,

Gao²,

Ding³

et al. 2021

J Gastrointest Oncol

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Background: Sorafenib, the first approved targeted therapy for advanced hepatocellular carcinoma (HCC), is often reported to comprised survival-benefit due to resistance. An underlying mechanism of resistance was proposed using bioinformatics analysis based on differentially expressed genes (DEGs) from microarrays.However, most DEGs were invalidated at both the expression level, and the role in causing resistance.Therefore, we conducted a bioinformatics analysis based on experimentally determined sorafenib-resistancerelated genes (SRRGs) to elucidate the mechanism of sorafenib resistance. Methods:The SRRGs, which have been experimentally determined to promote or inhibit resistance, were collected from published studies. The Database for Annotation, Visualization and Integrated Discovery (DAVID) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to perform Gene Ontology (GO) and pathway enrichment analysis, respectively. A corresponding protein-protein interaction network (PPI) was created using the Cytoscape software program, and network hub genes were proposed.Results: A total of 145 SRRGs, with 117 promoting and 28 inhibiting resistance, were identified. Cell proliferation, migration, development, response to oxygen levels, epithelial-to-mesenchymal transition (EMT), cell skeleton, protein function, and autophagy were all proposed as crucial gene functions related to resistance. The pathways related to cell proliferation or apoptosis, immune function, endocrine metabolism, stem cell function, and differentiation were identified as key resistance-related pathways. A total of 81 hub genes were proposed, including the following top 10 genes:

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Section: Discussionmentioning

confidence: 99%

Underlying mechanism of sorafenib resistance in hepatocellular carcinoma: a bioinformatics study based on validated resistance-related genes

Song¹,

Gao²,

Ding³

et al. 2021

J Gastrointest Oncol

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“…As a model for our investigation, we selected CXCR4 since it represents an important potential therapeutic target for various severe diseases involving the immune system, including cancer . In particular, recent studies demonstrated that targeting CXCR4 in association with anti-PDL1 antibody produces synergistic effect for restoring immune response to tumor . In this context, we have recently developed different peptides able to bind CXCR4 and to inhibit CXCL12-dependent migration with variable potencies ranging from low micromolar to low nanomolar. − Among these peptides, 1 (Figure ) has been chosen as the starting point of this study since it has a suitable affinity (IC 50 = 6.2 μM, Table ) for ligand-based NMR studies.…”

Section: Introductionmentioning

confidence: 99%

Ligand-Based NMR Study of C-X-C Chemokine Receptor Type 4 (CXCR4)–Ligand Interactions on Living Cancer Cells

et al. 2018

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Peptide-binding G protein-coupled receptors (GPCRs) are key effectors in numerous pathological and physiological pathways. The assessment of the receptor-bound conformation of a peptidic ligand within a membrane receptor such as a GPCR is of great impact for a rational drug design of more potent analogues. In this work, we applied multiple ligand-based nuclear magnetic resonance (NMR) methods to study the interaction of peptide heptamers, derived from the C-X-C Motif Chemokine 12 (CXCL12), and the C-X-C Chemokine Receptor Type 4 (CXCR4) on membranes of human T-Leukemia cells (CCRF-CEM cells). This study represents the first structural investigation reporting the receptor-bound conformation of a peptide to a GPCR directly on a living cell. The results obtained in the field of CXCL12/CXCR4 are proofs of concept, although important information for researchers dealing with the CXCR4 field arises. General application of the presented NMR methodologies is possible and surely may help to boost the development of new therapeutic agents targeting GPCRs.

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P0288 : CXCR4 inhibition reverts immunosuppressive tumor microenvironment and facilitates Anti-PD-1 immunotherapy in sorafenib-treated hepatocellular carcinoma

Cited by 2 publications

References 0 publications

Underlying mechanism of sorafenib resistance in hepatocellular carcinoma: a bioinformatics study based on validated resistance-related genes

Underlying mechanism of sorafenib resistance in hepatocellular carcinoma: a bioinformatics study based on validated resistance-related genes

Ligand-Based NMR Study of C-X-C Chemokine Receptor Type 4 (CXCR4)–Ligand Interactions on Living Cancer Cells

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