scholarly journals Lactate is a mediator of metabolic cooperation between stromal carcinoma associated fibroblasts and glycolytic tumor cells in the tumor microenvironment

2012 ◽  
Vol 318 (4) ◽  
pp. 326-335 ◽  
Author(s):  
Yanique I. Rattigan ◽  
Brijesh B. Patel ◽  
Ellen Ackerstaff ◽  
George Sukenick ◽  
Jason A. Koutcher ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Metabolic Cooperation ◽  
Carcinoma Associated Fibroblasts

scholarly journals The Blockade of Tumoral IL1β-Mediated Signaling in Normal Colonic Fibroblasts Sensitizes Tumor Cells to Chemotherapy and Prevents Inflammatory CAF Activation

2021 ◽  
Vol 22 (9) ◽  
pp. 4960
Author(s):  
Natalia Guillén Díaz-Maroto ◽  
Gemma Garcia-Vicién ◽  
Giovanna Polcaro ◽  
María Bañuls ◽  
Nerea Albert ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Cell Types ◽  
Colorectal Tumor ◽  
Cytotoxic Drugs ◽  
Differential Sensitivity ◽  
Paracrine Signaling ◽  
Inflammatory Phenotype ◽  
Heterotypic Interactions ◽  
Carcinoma Associated Fibroblasts

Heterotypic interactions between newly transformed cells and normal surrounding cells define tumor’s fate in incipient carcinomas. Once homeostasis has been lost, normal resident fibroblasts become carcinoma-associated fibroblasts, conferring protumorogenic properties on these normal cells. Here we describe the IL1β-mediated interplay between cancer cells and normal colonic myofibroblasts (NCFs), which bestows differential sensitivity to cytotoxic drugs on tumor cells. We used NCFs, their conditioned media (CM), and cocultures with tumor cells to characterize the IL1β-mediated crosstalk between both cell types. We silenced IL1β in tumor cells to demonstrate that such cells do not exert an influence on NCFs inflammatory phenotype. Our results shows that IL1β is overexpressed in cocultured tumor cells. IL1β enables paracrine signaling in myofibroblasts, converting them into inflammatory-CAFs (iCAF). IL1β-stimulated-NCF-CM induces migration and differential sensitivity to oxaliplatin in colorectal tumor cells. Such chemoprotective effect has not been evidenced for TGFβ1-driven NCFs. IL1β induces the loss of a myofibroblastic phenotype in NCFs and acquisition of iCAF traits. In conclusion, IL1β-secreted by cancer cells modify surrounding normal fibroblasts to confer protumorogenic features on them, particularly tolerance to cytotoxic drugs. The use of IL1β-blocking agents might help to avoid the iCAF traits acquisition and consequently to counteract the protumorogenic actions these cells.

scholarly journals Differentiated glioblastoma cells accelerate tumor progression by shaping the tumor microenvironment via CCN1-mediated macrophage infiltration

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Atsuhito Uneda ◽  
Kazuhiko Kurozumi ◽  
Atsushi Fujimura ◽  
Kentaro Fujii ◽  
Joji Ishida ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Tumor Cells ◽  
In Silico ◽  
Tumor Tissue ◽  
The Cancer Genome Atlas ◽  
Macrophage Infiltration ◽  
Macrophage Migration

AbstractGlioblastoma (GBM) is the most lethal primary brain tumor characterized by significant cellular heterogeneity, namely tumor cells, including GBM stem-like cells (GSCs) and differentiated GBM cells (DGCs), and non-tumor cells such as endothelial cells, vascular pericytes, macrophages, and other types of immune cells. GSCs are essential to drive tumor progression, whereas the biological roles of DGCs are largely unknown. In this study, we focused on the roles of DGCs in the tumor microenvironment. To this end, we extracted DGC-specific signature genes from transcriptomic profiles of matched pairs of in vitro GSC and DGC models. By evaluating the DGC signature using single cell data, we confirmed the presence of cell subpopulations emulated by in vitro culture models within a primary tumor. The DGC signature was correlated with the mesenchymal subtype and a poor prognosis in large GBM cohorts such as The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project. In silico signaling pathway analysis suggested a role of DGCs in macrophage infiltration. Consistent with in silico findings, in vitro DGC models promoted macrophage migration. In vivo, coimplantation of DGCs and GSCs reduced the survival of tumor xenograft-bearing mice and increased macrophage infiltration into tumor tissue compared with transplantation of GSCs alone. DGCs exhibited a significant increase in YAP/TAZ/TEAD activity compared with GSCs. CCN1, a transcriptional target of YAP/TAZ, was selected from the DGC signature as a candidate secreted protein involved in macrophage recruitment. In fact, CCN1 was secreted abundantly from DGCs, but not GSCs. DGCs promoted macrophage migration in vitro and macrophage infiltration into tumor tissue in vivo through secretion of CCN1. Collectively, these results demonstrate that DGCs contribute to GSC-dependent tumor progression by shaping a mesenchymal microenvironment via CCN1-mediated macrophage infiltration. This study provides new insight into the complex GBM microenvironment consisting of heterogeneous cells.

Mesenchymal Stem Cells and Cancer Stem Cells: An Overview of Tumor-Mesenchymal Stem Cell Interaction for therapeutic interventions

2021 ◽  
Vol 22 ◽  
Author(s):  
Soheila Montazersaheb ◽  
Ezzatollah Fathi ◽  
Ayoub Mamandi ◽  
Raheleh Farahzadi ◽  
Hamid Reza Heidari
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Microenvironment ◽  
Cancer Stem Cells ◽  
Tumor Cells ◽  
Cell Types ◽  
Cell Interaction ◽  
Therapeutic Interventions ◽  
Tumorigenic Potential ◽  
Different Types

: Tumors are made up of different types of cancer cells that contribute to tumor heterogeneity. Among these cells, cancer stem cells (CSCs) have a significant role in the onset of cancer and development. Like other stem cells, CSCs are characterized by the capacity for differentiation and self-renewal. A specific population of CSCs is constituted by mesenchymal stem cells (MSCs) that differentiate into mesoderm-specific cells. The pro-or anti-tumorigenic potential of MSCs on the proliferation and development of tumor cells has been reported as contradictory results. Also, tumor progression is specified by the corresponding tumor cells like the tumor microenvironment. The tumor microenvironment consists of a network of reciprocal cell types such as endothelial cells, immune cells, MSCs, and fibroblasts as well as growth factors, chemokines, and cytokines. In this review, recent findings related to the tumor microenvironment and associated cell populations, homing of MSCs to tumor sites, and interaction of MSCs with tumor cells will be discussed.

scholarly journals Assessment of phagocytic activity in live macrophages-tumor cells co-cultures by Confocal and Nomarski Microscopy

2017 ◽  
Vol 2 (1) ◽  
Author(s):  
Dalia Martinez-Marin ◽  
Courtney Jarvis ◽  
Thomas Nelius ◽  
Stéphanie Filleur
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Phagocytic Activity ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Functional Assay ◽  
Loss Of Function ◽  
Multiple Cancer

Abstract Macrophages have been recognized as the main inflammatory component of the tumor microenvironment. Although often considered as beneficial for tumor growth and disease progression, tumor-associated macrophages have also been shown to be detrimental to the tumor depending on the tumor microenvironment. Therefore, understanding the molecular interactions between macrophages and tumor cells in relation to macrophages functional activities such as phagocytosis is critical for a better comprehension of their tumor-modulating action. Still, the characterization of these molecular mechanisms in vivo remains complicated due to the extraordinary complexity of the tumor microenvironment and the broad range of tumor-associated macrophage functions. Thus, there is an increasing demand for in vitro methodologies to study the role of cell–cell interactions in the tumor microenvironment. In the present study, we have developed live co-cultures of macrophages and human prostate tumor cells to assess the phagocytic activity of macrophages using a combination of Confocal and Nomarski Microscopy. Using this model, we have emphasized that this is a sensitive, measurable, and highly reproducible functional assay. We have also highlighted that this assay can be applied to multiple cancer cell types and used as a selection tool for a variety of different types of phagocytosis agonists. Finally, combining with other studies such as gain/loss of function or signaling studies remains possible. A better understanding of the interactions between tumor cells and macrophages may lead to the identification of new therapeutic targets against cancer.

scholarly journals Semaphorin Signaling in Cancer-Associated Inflammation

2019 ◽  
Vol 20 (2) ◽  
pp. 377 ◽  
Author(s):  
Giulia Franzolin ◽  
Luca Tamagnone
Keyword(s):  
Immune Response ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Disease Progression ◽  
Tumor Cells ◽  
Cross Talk ◽  
Immune Cells ◽  
Major Element ◽  
Inflammatory Cells ◽  
Anti Cancer

The inflammatory and immune response elicited by the growth of cancer cells is a major element conditioning the tumor microenvironment, impinging on disease progression and patients’ prognosis. Semaphorin receptors are widely expressed in inflammatory cells, and their ligands are provided by tumor cells, featuring an intense signaling cross-talk at local and systemic levels. Moreover, diverse semaphorins control both cells of the innate and the antigen-specific immunity. Notably, semaphorin signals acting as inhibitors of anti-cancer immune response are often dysregulated in human tumors, and may represent potential therapeutic targets. In this mini-review, we provide a survey of the best known semaphorin regulators of inflammatory and immune cells, and discuss their functional impact in the tumor microenvironment.

scholarly journals P09.05 Plasma CD27, a surrogate of intratumoral CD27-CD70 interaction, correlates with immunotherapy resistance in renal cancer

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A30.1-A30
Author(s):  
N Benhamouda ◽  
I Sam ◽  
N Epaillard ◽  
A Gey ◽  
A Saldmann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Principal Investigator ◽  
Cell Phenotype ◽  
Metastatic Rcc ◽  
Research Grant

BackgroundCD70, a costimulatory molecule on antigen presenting cells, is known to activate CD27-expressing T cells. CD27-CD70 interaction leads to the release of soluble CD27 (sCD27). However, persistent interaction of CD27 and CD70 such as in chronic infection may exhaust the T cell pool and promote apoptosis. Surprisingly, our analysis based on TCGA database show that clear cell renal cell carcinoma (ccRCC) expresses the highest levels of CD70 among all solid tumors. Despite the important clinical efficacy of immunotherapy by anti-PD-1 in RCC patients, the overall response to anti-PD1 remains modest. The relationship between the CD27-CD70 interaction in the RCC and the response to immunotherapy is still unclear.Materials and MethodsTo study the CD27 and CD70 expression in the tumor microenvironment (TME), FFPE tumor tissues from 25 RCC patients were analysed using multiplex in situ immunofluorescence. 10 fresh RCC tumor samples were collected to analyse the phenotype of CD27+ T cells by flow cytometry and 4 samples were proceeded for single-cell RNA-seq analysis. A cohort of metastatic RCC patients (n = 35) treated by anti-PD-1 were enrolled for the measurement of plasma sCD27 by ELISA and the survival analysis is also realized.ResultsIn the TME, we demonstrated that CD27+ T cells interact with CD70-expressing tumor cells. In fresh tumors from RCC patients, CD27+ T cells express higher levels of cleaved caspase 3 (a classical marker of apoptosis) than CD27- T cells. We confirmed the apoptotic signature (BAX, FASLG, BCL2L11, CYCS, FBXO32, LGALS1, PIK3R1, TERF1, TXNIP, CDKN2A) of CD27+ T cells by single-cell RNAseq analysis. CD27+T cells also had a tissue resident memory T cell phenotype with enriched gene expression of ITGAE, PRDM1, RBPJ and ZNF683. Moreover, CD27+T cells display an exhaustion phenotype with the expression of multiple inhibitory receptors gene signature (PDCD1, CTLA4, HAVCR2, LAG3, etc). Besides, intratumoral CD27-CD70 interaction significantly correlates with plasma sCD27 concentration in RCC (p = 0.0017). In metastatic RCC patients treated with anti-PD-1, higher levels of sCD27 predict poor overall survival (p = 0.037), while it did not correlate with inflammatory markers or clinical prognostic criteria.ConclusionsIn conclusion, we demonstrated that sCD27, a surrogate of T cell dysfunction in tumors likely induced by persistent interactions of CD27+T cells and CD70-expressing tumor cells, is a predictive biomarker of resistance to immunotherapy in mRCC. To our knowledge, this is the first report showing that a peripheral blood biomarker may reflect certain aspects of the tumor-host interaction in the tumor microenvironment. Given the frequent expression of CD70 and CD27 in solid tumors, our findings may be further extended to other types of tumors. CD70-CD27 interaction could thus be considered as a mechanism of tumor escape, but also a novel therapeutic target in cancers.Disclosure InformationN. Benhamouda: None. I. Sam: None. N. Epaillard: None. A. Gey: None. A. Saldmann: None. J. Pineau: None. M. Hasan: None. V. Verkarre: None. V. Libri: None. S. Mella: None. C. Granier: None. C. Broudin: None. P. Ravel: None. B. Jabla: None. N. Chaput: None. L. Albiges: None. Y. Vano: None. O. Adotevi: None. S. Oudard: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; SIRIC CARPEM, FONCER. E. Tartour: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Fondation ARC, INCA PLBio, Labex Immuno-Oncology, SIRIC CARPEM, FONCER, IDEX université de Paris, Inserm Transfert.

scholarly journals 799 Neoantigen-cytokine-chemokine multifunctional natural killer cell engager for immunotherapy of solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A834-A834
Author(s):  
Xue Yao ◽  
Sandro Matosevic
Keyword(s):  
Tumor Microenvironment ◽  
Cell Therapy ◽  
Nk Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Nk Cell Therapy

BackgroundThe effectiveness of natural killer (NK) cell-based immunotherapy against solid tumors is limited by the lack of specific antigens and the immunosuppressive tumor microenvironment (TME). Glioblastoma multiforme (GBM) is one such heavily immunosuppressive tumor that has been particularly hard to target and remains without a viable treatment. The development of novel approaches to enhance the efficacy of NK cells against GBM is urgently needed. NK cell engagers (NKCE) have been developed to enhance the efficacy of NK cell therapy.MethodsTo improve the clinical efficacy of NK cell therapy, we are developing a new generation of multi-specific killer engagers, which consists of a neoantigen-targeting moiety, together with cytokine and chemokine-producing domains. Neoantigens are new antigens formed specifically in tumor cells due to genome mutations, making them highly specific tools to target tumor cells. Our engager has been designed to target Wilms' tumor-1 (WT-1), a highly specific antigen overexpressed in GBM among other solid tumors. This is done through the generation of an scFv specific targeting the complex of WT-1126-134/HLA-A*02:01 on the surface of GBM. On the NK cell side, the engager is designed to target the activating receptor NKp46. Incorporation of the cytokine IL-15 within the engager supports the maturation, persistence, and expansion of NK cells in vivo while favoring their proliferation and survival in the tumor microenvironment. Additionally, our data indicated that the chemokine CXCL10 plays an important role in the infiltration of NK cells into GBM, however, GBM tumors produce low levels of this chemokine. Incorporation of a CXCL10-producing function into our engager supports intratumoral NK cell trafficking by promoting, through their synthetic production, increased levels of CXCL10 locally in the tumor microenvironment.ResultsCollectively, this has resulted in a novel multifunctional NK cell engager, combining neoantigen-cytokine-chemokine elements fused to an activating domain-specific to NK cells, and we have investigated its ability to support and enhance NK cell-mediated cytotoxicity against solid tumors in vitro and in vivo against patient-derived GBM models. The multi-specific engager shows both high tumor specificity, as well as the ability to overcome NK cell dysfunction encountered in the GBM TME.ConclusionsWe hypothesize that taking advantage of our multi-functional engager, NK cells will exhibit superior ex vivo expansion, infiltration, and antitumor activity in the treatment of GBM and other solid tumors.

scholarly journals Hypoxia-inducible factor (HIF): fuel for cancer progression

2021 ◽  
Vol 14 ◽  
Author(s):  
Saurabh Satija ◽  
Harpreet Kaur ◽  
Murtaza M. Tambuwala ◽  
Prabal Sharma ◽  
Manish Vyas ◽  
...  
Keyword(s):  
Biological Sciences ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Oxygen Deficiency ◽  
Hypoxia Inducible Factor ◽  
Transcription Factor Activation ◽  
Underlying Mechanisms ◽  
Adaptive Reactions

Hypoxia is an integral part of tumor microenvironment, caused primarily due to rapidly multiplying tumor cells and a lack of proper blood supply. Among the major hypoxic pathways, HIF-1 transcription factor activation is one of the widely investigated pathways in the hypoxic tumor microenvironment (TME). HIF-1 is known to activate several adaptive reactions in response to oxygen deficiency in tumor cells. HIF-1 has two subunits, HIF-1β (constitutive) and HIF-1α (inducible). The HIF-1α expression is largely regulated via various cytokines (through PI3K-ACT-mTOR signals), which involves the cascading of several growth factors and oncogenic cascades. These events lead to the loss of cellular tumor suppressant activity through changes in the level of oxygen via oxygen-dependent and oxygen-independent pathways. The significant and crucial role of HIF in cancer progression and its underlying mechanisms have gained much attention lately among the translational researchers in the fields of cancer and biological sciences, which have enabled them to correlate these mchanisms with various other disease modalities. In the present review, we have summarized the key findings related to the role of HIF in the progression of tumors.

scholarly journals Immunomodulatory Effects of Tryptophan Metabolism in the Glioma Tumor Microenvironment

2021 ◽  
Vol 12 ◽  
Author(s):  
Yang Xu ◽  
Huikai Zhang ◽  
Qian Sun ◽  
Rongxin Geng ◽  
Fanen Yuan ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Immune Regulation ◽  
Acid Metabolism ◽  
Regulatory Mechanism ◽  
Term Treatment ◽  
Tryptophan Metabolism ◽  
Long Term Treatment ◽  
Regulation Mechanisms

Gliomas are the most common primary malignant tumor in adults’ central nervous system. While current research on glioma treatment is advancing rapidly, there is still no breakthrough in long-term treatment. Abnormalities in the immune regulatory mechanism in the tumor microenvironment are essential to tumor cell survival. The alteration of amino acid metabolism is considered a sign of tumor cells, significantly impacting tumor cells and immune regulation mechanisms in the tumor microenvironment. Despite the fact that the metabolism of tryptophan in tumors is currently discussed in the literature, we herein focused on reviewing the immune regulation of tryptophan metabolism in the tumor microenvironment of gliomas and analyzed possible immune targets. The objective is to identify potential targets for the treatment of glioma and improve the efficiency of immunotherapy.

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