AMD3100/Plerixafor overcomes immune inhibition by the CXCL12–KRT19 coating on pancreatic and colorectal cancer cells

Fearon, Douglas T.; Janowitz, Tobias

doi:10.1038/s41416-021-01315-y

Cited by 13 publications

(5 citation statements)

References 10 publications

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“…Continuous infusion of AMD3100 induced intratumoral T lymphocyte aggregation in patients. It unexpectedly activated the B-cell response, and most patients showed an enhanced T, B cell response after only one week [ 257 , 310 ]. Based on the immunosuppressive microenvironment of PC, some patients have little or no response to immunotherapy.…”

Section: Background Knowledge Of Cafsmentioning

confidence: 99%

Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials

Zhang,

Yue,

Chen

et al. 2023

Mol Cancer

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Despite centuries since the discovery and study of cancer, cancer is still a lethal and intractable health issue worldwide. Cancer-associated fibroblasts (CAFs) have gained much attention as a pivotal component of the tumor microenvironment. The versatility and sophisticated mechanisms of CAFs in facilitating cancer progression have been elucidated extensively, including promoting cancer angiogenesis and metastasis, inducing drug resistance, reshaping the extracellular matrix, and developing an immunosuppressive microenvironment. Owing to their robust tumor-promoting function, CAFs are considered a promising target for oncotherapy. However, CAFs are a highly heterogeneous group of cells. Some subpopulations exert an inhibitory role in tumor growth, which implies that CAF-targeting approaches must be more precise and individualized. This review comprehensively summarize the origin, phenotypical, and functional heterogeneity of CAFs. More importantly, we underscore advances in strategies and clinical trials to target CAF in various cancers, and we also summarize progressions of CAF in cancer immunotherapy.

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Section: Background Knowledge Of Cafsmentioning

confidence: 99%

Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials

Zhang,

Yue,

Chen

et al. 2023

Mol Cancer

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“…NOX-A12 is a novel RNA aptamer that binds CXCL12 in two key positions, blocking binding of the chemokine to its receptors and dislodging bound CXCL12 from cell surfaces [ 79 ]. NOX-A12 has synergized with PD-1 blockade by enhancing T-cell infiltration in preclinical models [ 87 ], leading to an exploratory phase 1B study with a small cohort of 11 colorectal and 9 pancreatic cancer patients, where a combination of NOX-A12 with the PD-1 inhibitor pembrolizumab induced T helper type 1 (Th1) immune responses and prolonged disease stabilization in a minority of patients, supporting previous findings that the CXCL12/CXCR4 axis is important in immune evasion in pancreatic cancer [ 88 ].…”

Section: Therapeutic Targeting Of Cxcl12/cxcr4 In Pancreatic Cancermentioning

confidence: 99%

CXCL12 in Pancreatic Cancer: Its Function and Potential as a Therapeutic Drug Target

Malik

Westcott

Brekken

et al. 2021

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is a disease with limited therapeutic options and dismal long-term survival. The unique tumor environment of PDAC, consisting of desmoplastic stroma, immune suppressive cells, and activated fibroblasts, contributes to its resistance to therapy. Activated fibroblasts (cancer-associated fibroblasts and pancreatic stellate cells) secrete chemokines and growth factors that support PDAC growth, spread, chemoresistance, and immune evasion. In this review, we focus on one such chemokine, CXCL12, secreted by the cancer-associated fibroblasts and discuss its contribution to several of the classical hallmarks of PDAC and other tumors. We review the various therapeutic approaches in development to target CXCL12 signaling in PDAC. Finally, we propose an unconventional use of tipifarnib, a farnesyl transferase inhibitor, to inhibit CXCL12 production in PDAC.

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“…Few studies have explored the effects of the other two (KRT19, and SPANXB1) in immunoregulation. However, interrupting expression of KRT19 in mouse tumors prevented the formation of the CXCL12–KRT19 coating, allowed the accumulation of T cells ( 78 ), suggesting a possible role of KRT19 in immunoregulation. Considering low CD8+ T cell infiltration often associated with poor outcome and CD8+ T cell is one of the major immune cell determinants of the brain TME ( 47 , 71 , 74 ), the negative correlation between the identified genes (KRT19, FKBP10 and SPANXB1) and CD8+ T cell infiltration suggests the immunosuppressive and metastasis-promoting effects in BCBM.…”

Section: Discussionmentioning

confidence: 99%

Screening and Identification of Novel Potential Biomarkers for Breast Cancer Brain Metastases

et al. 2022

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Brain metastases represent a major cause of mortality among patients with breast cancer, and few effective targeted treatment options are currently available. Development of new biomarkers and therapeutic targets for breast cancer brain metastases (BCBM) is therefore urgently needed. In this study, we compared the gene expression profiles of the brain metastatic cell line MDA-MB-231-BR (231-BR) and its parental MDA-MB-231, and identified a total of 84 genes in the primary screening through a series of bioinformatic analyses, including construction of protein-protein interaction (PPI) networks by STRING database, identification of hub genes by applying of MCODE and Cytohubba algorithms, identification of leading-edge subsets of Gene Set Enrichment Analysis (GSEA), and identification of most up-regulated genes. Eight genes were identified as candidate genes due to their elevated expression in brain metastatic 231-BR cells and prognostic values in patients with BCBM. Then we knocked down the eight individual candidate genes in 231-BR cells and evaluated their impact on cell migration through a wound-healing assay, and four of them (KRT19, FKBP10, GSK3B and SPANXB1) were finally identified as key genes. Furthermore, the expression of individual key genes showed a correlation with the infiltration of major immune cells in the brain tumor microenvironment (TME) as analyzed by Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA), suggesting possible roles of them in regulation of the tumor immune response in TME. Therefore, the present work may provide new potential biomarkers for BCBM. Additionally, using GSEA, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Enrichment Analysis, we determined the top enriched cellular functions or pathways in 231-BR cells, which may help better understand the biology governing the development and progression of BCBM.

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AMD3100/Plerixafor overcomes immune inhibition by the CXCL12–KRT19 coating on pancreatic and colorectal cancer cells

Cited by 13 publications

References 10 publications

Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials

Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials

CXCL12 in Pancreatic Cancer: Its Function and Potential as a Therapeutic Drug Target

Screening and Identification of Novel Potential Biomarkers for Breast Cancer Brain Metastases

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