Cancer Stemness Meets Immunity: From Mechanism to Therapy

Chen, Peiwen; Hsu, Wen‐Hao; Han, Jiaying; Xia, Yan; DePinho, Ronald A.

doi:10.1016/j.celrep.2020.108597

Cited by 141 publications

(131 citation statements)

References 182 publications

(200 reference statements)

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“…The MES subtype microenvironment includes endothelial cell markers and enrichment of macrophages, microglia, CD4 T cells, and neutrophils, but with a decrease in activated cytotoxic natural killer (NK) cells [ 31 , 66 , 71 ]. An increase in macrophages and microglial cells are found in the TME of early GBM recurrences, consistent with a model in which the GME regulates GBM cellular phenotype and drives GSC plasticity [ 72 ] and therapy-resistant tumors [ 73 ] (reviewed by Chen et al [ 74 ]). New light has been shed upon the MES–GBM subtype through comprehensive genomic and phosphor–proteomic analyses of 99 GBM samples, which showed upregulation of hypoxia and angiogenesis pathways [ 25 ], together with activation and polarization to the M2 macrophage phenotype.…”

Section: Glioblastoma Microenvironment (Gme)supporting

confidence: 79%

An Update on Glioblastoma Biology, Genetics, and Current Therapies: Novel Inhibitors of the G Protein-Coupled Receptor CCR5

Turnšek

Jiao

Novak

et al. 2021

IJMS

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The mechanisms governing therapeutic resistance of the most aggressive and lethal primary brain tumor in adults, glioblastoma, have increasingly focused on tumor stem cells. These cells, protected by the periarteriolar hypoxic GSC niche, contribute to the poor efficacy of standard of care treatment of glioblastoma. Integrated proteogenomic and metabolomic analyses of glioblastoma tissues and single cells have revealed insights into the complex heterogeneity of glioblastoma and stromal cells, comprising its tumor microenvironment (TME). An additional factor, which isdriving poor therapy response is the distinct genetic drivers in each patient’s tumor, providing the rationale for a more individualized or personalized approach to treatment. We recently reported that the G protein-coupled receptor CCR5, which contributes to stem cell expansion in other cancers, is overexpressed in glioblastoma cells. Overexpression of the CCR5 ligand CCL5 (RANTES) in glioblastoma completes a potential autocrine activation loop to promote tumor proliferation and invasion. CCL5 was not expressed in glioblastoma stem cells, suggesting a need for paracrine activation of CCR5 signaling by the stromal cells. TME-associated immune cells, such as resident microglia, infiltrating macrophages, T cells, and mesenchymal stem cells, possibly release CCR5 ligands, providing heterologous signaling between stromal and glioblastoma stem cells. Herein, we review current therapies for glioblastoma, the role of CCR5 in other cancers, and the potential role for CCR5 inhibitors in the treatment of glioblastoma.

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Section: Glioblastoma Microenvironment (Gme)supporting

confidence: 79%

An Update on Glioblastoma Biology, Genetics, and Current Therapies: Novel Inhibitors of the G Protein-Coupled Receptor CCR5

Turnšek

Jiao

Novak

et al. 2021

IJMS

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“…Furthermore, TAMs actively produce several proteolytic enzymes, such as matrix metalloproteases, serine proteases and cathepsins, thereby enhancing the remodeling of the tumor stroma and favoring the metastatic process of cancer cells (Liguori et al 2011 ; Zhang et al 2017 ; Sangaletti et al 2014 ; Chen et al 2011 ; Steenbrugge et al 2018 ; Wang et al 2011 , 2018 ; Aras and Zaidi 2017 ). While it is well established that TAMs display these supporting functions on the proliferating cancer cells, relatively few studies have addressed the impact of TAMs on the specific population of tumor-initiating cells or Cancer Stem Cells (CSCs) (Chen et al 2021 ; Raggi et al 2016 ; Aramini et al 2021 ; Fan et al 2014 ; Jinushi et al 2011 ; Osman et al 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Macrophages and cancer stem cells: a malevolent alliance

Allavena

Digifico

Belgiovine

2021

Mol Med

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Myeloid cells infiltrating tumors are gaining ever growing attention in the last years because their pro-tumor and immunosuppressive functions are relevant for disease progression and therapeutic responses. The functional ambiguity of tumor-associated macrophages (TAMs), mostly promoting tumor evolution, is a challenging hurdle. This is even more evident in the case of cancer stem cells (CSCs); as active participants in the specialized environment of the cancer stem cell niche, TAMs initiate a reciprocal conversation with CSCs. TAMs contribute to protect CSCs from the hostile environment (exogenous insults, toxic compounds, attacks from the immune cells), and produce several biologically active mediators that modulate crucial developmental pathways that sustain cancer cell stemness. In this review, we have focused our attention on the interaction between TAMs and CSCs; we describe how TAMs impact on CSC biology and, in turn, how CSCs exploit the tissue trophic activity of macrophages to survive and progress. Since CSCs are responsible for therapy resistance and tumor recurrence, they are important therapeutic targets. In view of the recent success in oncology obtained by stimulating the immune system, we discuss some macrophage-targeted therapeutic strategies that may also affect the CSCs and interrupt their malevolent alliance.

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“…Because infiltrating M2 type macrophages are strongly connected with the histologic pattern correlating within the same tumor, heterogeneity of the immune stroma appears to be regulated on a micro-anatomic level and not governed by systemic immune changes. Interestingly, there is possibly a regulatory link in the other direction as well, with M2 macrophages redirecting tumor cells to undergo a stemness program [24,33].…”

Section: Discussionmentioning

confidence: 99%

“…In multiple solid tumors, "cancer stem cells" defined as self-renewing cells facilitating tumor initiation and promoting metastasis and therapeutic resistance have been identified that reciprocally interact with immune cells, including tumor associated macrophages [24].…”

Section: Introductionmentioning

confidence: 99%

Prognostic Gene Expression, Stemness and Immune Microenvironment in Pediatric Tumors

Stahl

Knoll

Gentles

et al. 2021

Cancers

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Pediatric tumors frequently arise from embryonal cells, often displaying a stem cell-like (“small round blue”) morphology in tissue sections. Because recently “stemness” has been associated with a poor immune response in tumors, we investigated the association of prognostic gene expression, stemness and the immune microenvironment systematically using transcriptomes of 4068 tumors occurring mostly at the pediatric and young adult age. While the prognostic landscape of gene expression (PRECOG) and infiltrating immune cell types (CIBERSORT) is similar to that of tumor entities occurring mainly in adults, the patterns are distinct for each diagnostic entity. A high stemness score (mRNAsi) correlates with clinical and morphologic subtype in Wilms tumors, neuroblastomas, synovial sarcomas, atypical teratoid rhabdoid tumors and germ cell tumors. In neuroblastomas, a high mRNAsi is associated with shortened overall survival. In Wilms tumors a high mRNAsi correlates with blastemal morphology, whereas tumors with predominant epithelial or stromal differentiation have a low mRNAsi and a high percentage of M2 type macrophages. This could be validated in Wilms tumor tissue (n = 78). Here, blastemal areas are low in M2 macrophage infiltrates, while nearby stromal differentiated areas contain abundant M2 macrophages, suggesting local microanatomic regulation of the immune response.

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Cancer Stemness Meets Immunity: From Mechanism to Therapy

Cited by 141 publications

References 182 publications

An Update on Glioblastoma Biology, Genetics, and Current Therapies: Novel Inhibitors of the G Protein-Coupled Receptor CCR5

An Update on Glioblastoma Biology, Genetics, and Current Therapies: Novel Inhibitors of the G Protein-Coupled Receptor CCR5

Macrophages and cancer stem cells: a malevolent alliance

Prognostic Gene Expression, Stemness and Immune Microenvironment in Pediatric Tumors

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