Cancer-Associated Fibroblast Heterogeneity: A Factor That Cannot Be Ignored in Immune Microenvironment Remodeling

Cancer-associated fibroblasts (CAFs) are important, highly heterogeneous components of the tumor extracellular matrix that have different origins and express a diverse set of biomarkers. Different subtypes of CAFs participate in the immune regulation of the tumor microenvironment (TME). In addition to their role in supporting stromal cells, CAFs have multiple immunosuppressive functions, via membrane and secretory patterns, against anti-tumor immunity. The inhibition of CAFs function and anti-TME therapy targeting CAFs provides new adjuvant means for immunotherapy. In this review, we outline the emerging understanding of CAFs with a particular emphasis on their origin and heterogeneity, different mechanisms of their regulation, as well as their direct or indirect effect on immune cells that leads to immunosuppression.

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Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives

Molecular Cancer ◽

10.1186/s12943-021-01428-1 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Xiaoqi Mao ◽

Jin Xu ◽

Wei Wang ◽

Chen Liang ◽

Jie Hua ◽

...

Keyword(s):

Tumor Microenvironment ◽

Immune Cells ◽

Immune Cell ◽

Critical Role ◽

Cancer Associated Fibroblasts ◽

Cell Of Origin ◽

Future Perspectives ◽

Immune Microenvironment ◽

New Findings ◽

Essential Components

AbstractCancer-associated fibroblasts (CAFs), a stromal cell population with cell-of-origin, phenotypic and functional heterogeneity, are the most essential components of the tumor microenvironment (TME). Through multiple pathways, activated CAFs can promote tumor growth, angiogenesis, invasion and metastasis, along with extracellular matrix (ECM) remodeling and even chemoresistance. Numerous previous studies have confirmed the critical role of the interaction between CAFs and tumor cells in tumorigenesis and development. However, recently, the mutual effects of CAFs and the tumor immune microenvironment (TIME) have been identified as another key factor in promoting tumor progression. The TIME mainly consists of distinct immune cell populations in tumor islets and is highly associated with the antitumor immunological state in the TME. CAFs interact with tumor-infiltrating immune cells as well as other immune components within the TIME via the secretion of various cytokines, growth factors, chemokines, exosomes and other effector molecules, consequently shaping an immunosuppressive TME that enables cancer cells to evade surveillance of the immune system. In-depth studies of CAFs and immune microenvironment interactions, particularly the complicated mechanisms connecting CAFs with immune cells, might provide novel strategies for subsequent targeted immunotherapies. Herein, we shed light on recent advances regarding the direct and indirect crosstalk between CAFs and infiltrating immune cells and further summarize the possible immunoinhibitory mechanisms induced by CAFs in the TME. In addition, we present current related CAF-targeting immunotherapies and briefly describe some future perspectives on CAF research in the end.

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Regulation of tumor immune microenvironment by sphingolipids and lysophosphatidic acid

Current Drug Targets ◽

10.2174/1389450122666211208111833 ◽

2021 ◽

Vol 22 ◽

Author(s):

Supriya Vishwakarma ◽

Neha Arya ◽

Ashok Kumar

Keyword(s):

Extracellular Matrix ◽

Tumor Microenvironment ◽

Lysophosphatidic Acid ◽

Immune Cells ◽

Cancer Therapeutics ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment ◽

Sphingosine 1 Phosphate ◽

Patient Prognosis

: The tumor microenvironment (TME) consists of cancer cells that interact with stromal components such as the extracellular matrix, blood, and lymphatic networks, fibroblasts, adipocytes, and the cells of the immune system. Further, the tumor immune microenvironment, majorly represented by the tumor-infiltrating immune cells (TIIC), plays an important role in cancer therapeutics and patient prognosis. In fact, a high density of TIICs within the tumor microenvironment is known to be associated with better outcomes in several types of cancers. Towards this, two bioactive lipid molecules, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) regulate the homing of immune cells to the TME. In the present review, we will uncover the role of LPA and S1P signaling in the tumor immune environment, highlighting the latest progress in this field.

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Integrin Regulation of CAF Differentiation and Function

Cancers ◽

10.3390/cancers11050715 ◽

2019 ◽

Vol 11 (5) ◽

pp. 715 ◽

Cited By ~ 7

Author(s):

C. Michael DiPersio ◽

Livingston Van De Water

Keyword(s):

Extracellular Matrix ◽

Tumor Microenvironment ◽

Tumor Cells ◽

Stromal Cells ◽

Inflammatory Cells ◽

Cell Types ◽

Extensive Literature ◽

Cancer Associated Fibroblasts ◽

Epithelial Tumor ◽

And Function

Extensive remodeling of the extracellular matrix, together with paracrine communication between tumor cells and stromal cells, contribute to an “activated” tumor microenvironment that supports malignant growth and progression. These stromal cells include inflammatory cells, endothelial cells, and cancer-associated fibroblasts (CAFs). Integrins are expressed on all tumor and stromal cell types where they regulate both cell adhesion and bidirectional signal transduction across the cell membrane. In this capacity, integrins control pro-tumorigenic cell autonomous functions such as growth and survival, as well as paracrine crosstalk between tumor cells and stromal cells. The myofibroblast-like properties of cancer-associated fibroblasts (CAFs), such as robust contractility and extracellular matrix (ECM) deposition, allow them to generate both chemical and mechanical signals that support invasive tumor growth. In this review, we discuss the roles of integrins in regulating the ability of CAFs to generate and respond to extracellular cues in the tumor microenvironment. Since functions of specific integrins in CAFs are only beginning to emerge, we take advantage of a more extensive literature on how integrins regulate wound myofibroblast differentiation and function, as some of these integrin functions are likely to extrapolate to CAFs within the tumor microenvironment. In addition, we discuss the roles that integrins play in controlling paracrine signals that emanate from epithelial/tumor cells to stimulate fibroblasts/CAFs.

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The effect of PEGylation on the efficacy and uptake of an immunostimulatory nanoparticle in the tumor immune microenvironment

Nanoscale Advances ◽

10.1039/d1na00308a ◽

2021 ◽

Author(s):

Wyatt M. Becicka ◽

Peter Bielecki ◽

Morgan Lorkowski ◽

Taylor J. Moon ◽

Yahan Zhang ◽

...

Keyword(s):

Tumor Microenvironment ◽

Immune Cells ◽

Innate Immune ◽

Innate Immune Cells ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment ◽

Immunosuppressive Tumor Microenvironment

The efficacy of immunotherapies is often limited by the immunosuppressive tumor microenvironment, which is populated with dysfunctional innate immune cells. To reprogram the tumor-resident innate immune cells, we developed an...

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Toward Normalization of the Tumor Microenvironment for Cancer Therapy

Integrative Cancer Therapies ◽

10.1177/1534735419862352 ◽

2019 ◽

Vol 18 ◽

pp. 153473541986235 ◽

Cited By ~ 5

Author(s):

Jie Zheng ◽

Peng Gao

Keyword(s):

Stem Cells ◽

Extracellular Matrix ◽

Tumor Microenvironment ◽

Immune Cells ◽

Normal Tissue ◽

Cancer Growth ◽

Tissue Architecture ◽

Action Mechanisms ◽

Anticancer Effects ◽

Complex Ecosystem

The tumor microenvironment (TME) is a complex ecosystem, including blood vessels, immune cells, fibroblasts, extracellular matrix, cytokines, hormones, and so on. The TME differs from the normal tissue environment (NTE) in many aspects, such as tissue architecture, chronic inflammation, level of oxygen and pH, nutritional state of the cells, as well as tissue firmness. The NTE can inhibit the growth of cancer at the early tumorigenesis phase, whereas the TME promotes the growth of cancer in general, although it may have some anticancer effects. In particular, the TME plays a crucial role in the generation and maintenance of cancer stem cells, which lie at the root of cancer growth. Therefore, normalization of the TME to the NTE may inhibit cancer growth or improve cancer therapeutic efficiency. This review focuses on the recent emerging approaches for this normalization and the action mechanisms.

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Mesenchymal Stromal-Like Cells in the Glioma Microenvironment: What Are These Cells?

Cancers ◽

10.3390/cancers12092628 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2628

Author(s):

Anne Clavreul ◽

Philippe Menei

Keyword(s):

Blood Vessels ◽

Immune Cells ◽

Stromal Cells ◽

Low Ph ◽

Cancer Associated Fibroblasts ◽

Tumor Resistance ◽

Interstitial Pressure ◽

Close Proximity ◽

Cellular Components ◽

Glioma Microenvironment

The glioma microenvironment is a critical regulator of tumor progression. It contains different cellular components such as blood vessels, immune cells, and neuroglial cells. It also contains non-cellular components, such as the extracellular matrix, extracellular vesicles, and cytokines, and has certain physicochemical properties, such as low pH, hypoxia, elevated interstitial pressure, and impaired perfusion. This review focuses on a particular type of cells recently identified in the glioma microenvironment: glioma-associated stromal cells (GASCs). This is just one of a number of names given to these mesenchymal stromal-like cells, which have phenotypic and functional properties similar to those of mesenchymal stem cells and cancer-associated fibroblasts. Their close proximity to blood vessels may provide a permissive environment, facilitating angiogenesis, invasion, and tumor growth. Additional studies are required to characterize these cells further and to analyze their role in tumor resistance and recurrence.

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Macrophages in Osteosarcoma Immune Microenvironment: Implications for Immunotherapy

Frontiers in Oncology ◽

10.3389/fonc.2020.586580 ◽

2020 ◽

Vol 10 ◽

Author(s):

Zhong-Wei Luo ◽

Pan-Pan Liu ◽

Zhen-Xing Wang ◽

Chun-Yuan Chen ◽

Hui Xie

Keyword(s):

Overall Survival ◽

Tumor Microenvironment ◽

Bone Tumor ◽

Immune Cells ◽

Therapeutic Approaches ◽

Immune Microenvironment ◽

Primary Bone Tumor ◽

Promising Strategy ◽

Primary Bone ◽

Malignant Primary Bone Tumor

Osteosarcoma is a malignant primary bone tumor commonly occurring in children and adolescents. The treatment of local osteosarcoma is mainly based on surgical resection and chemotherapy, whereas the improvement of overall survival remains stagnant, especially in recurrent or metastatic cases. Tumor microenvironment (TME) is closely related to the occurrence and development of tumors, and macrophages are among the most abundant immune cells in the TME. Due to their vital roles in tumor progression, macrophages have gained increasing attention as the new target of tumor immunotherapy. In this review, we present a brief overview of macrophages in the TME and highlight the clinical significance of macrophages and their roles in the initiation and progression of osteosarcoma. Finally, we summarize the therapeutic approaches targeting macrophage, which represent a promising strategy in osteosarcoma therapies.

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Matrix Remodeling and Hyaluronan Production by Myofibroblasts and Cancer-Associated Fibroblasts in 3D Collagen Matrices

Gels ◽

10.3390/gels6040033 ◽

2020 ◽

Vol 6 (4) ◽

pp. 33

Author(s):

Jiranuwat Sapudom ◽

Claudia Damaris Müller ◽

Khiet-Tam Nguyen ◽

Steve Martin ◽

Ulf Anderegg ◽

...

Keyword(s):

Extracellular Matrix ◽

Tumor Microenvironment ◽

Average Molecular Weight ◽

Cell Types ◽

Dermal Fibroblasts ◽

Matrix Remodeling ◽

Cancer Associated Fibroblasts ◽

Collagen Matrices ◽

3D Collagen ◽

Tgf Β1

The tumor microenvironment is a key modulator in cancer progression and has become a novel target in cancer therapy. An increase in hyaluronan (HA) accumulation and metabolism can be found in advancing tumor progression and are often associated with aggressive malignancy, drug resistance and poor prognosis. Wound-healing related myofibroblasts or activated cancer-associated fibroblasts (CAF) are assumed to be the major sources of HA. Both cell types are capable to synthesize new matrix components as well as reorganize the extracellular matrix. However, to which extent myofibroblasts and CAF perform these actions are still unclear. In this work, we investigated the matrix remodeling and HA production potential in normal human dermal fibroblasts (NHFB) and CAF in the absence and presence of transforming growth factor beta -1 (TGF-β1), with TGF-β1 being a major factor of regulating fibroblast differentiation. Three-dimensional (3D) collagen matrix was utilized to mimic the extracellular matrix of the tumor microenvironment. We found that CAF appeared to response insensitively towards TGF-β1 in terms of cell proliferation and matrix remodeling when compared to NHFB. In regards of HA production, we found that both cell types were capable to produce matrix bound HA, rather than a soluble counterpart, in response to TGF-β1. However, activated CAF demonstrated higher HA production when compared to myofibroblasts. The average molecular weight of produced HA was found in the range of 480 kDa for both cells. By analyzing gene expression of HA metabolizing enzymes, namely hyaluronan synthase (HAS1-3) and hyaluronidase (HYAL1-3) isoforms, we found expression of specific isoforms in dependence of TGF-β1 present in both cells. In addition, HAS2 and HYAL1 are highly expressed in CAF, which might contribute to a higher production and degradation of HA in CAF matrix. Overall, our results suggested a distinct behavior of NHFB and CAF in 3D collagen matrices in the presence of TGF-β1 in terms of matrix remodeling and HA production pointing to a specific impact on tumor modulation.

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Nanoparticle-based delivery systems modulate the tumor microenvironment in pancreatic cancer for enhanced therapy

Journal of Nanobiotechnology ◽

10.1186/s12951-021-01134-6 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Ming Jia ◽

Dan Zhang ◽

Chunxiang Zhang ◽

Chunhong Li

Keyword(s):

Pancreatic Cancer ◽

Tumor Microenvironment ◽

Immune Cells ◽

Malignant Tumors ◽

Treatment Strategies ◽

Delivery Systems ◽

Cancer Microenvironment ◽

Cancer Associated Fibroblasts ◽

Hypoxic Environment ◽

Promising Therapeutic Approach

AbstractPancreatic cancer is one of the most lethal malignant tumors with a low survival rate, partly because the tumor microenvironment (TME), which consists of extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), immune cells, and vascular systems, prevents effective drug delivery and chemoradiotherapy. Thus, modulating the microenvironment of pancreatic cancer is considered a promising therapeutic approach. Since nanoparticles are one of the most effective cancer treatment strategies, several nano-delivery platforms have been developed to regulate the TME and enhance treatment. Here, we summarize the latest advances in nano-delivery systems that alter the TME in pancreatic cancer by depleting ECM, inhibiting CAFs, reversing immunosuppression, promoting angiogenesis, or improving the hypoxic environment. We also discuss promising new targets for such systems. This review is expected to improve our understanding of how to modulate the pancreatic cancer microenvironment and guide the development of new therapies. Graphical Abstract

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Interaction between Fibroblasts and Immune Cells Following DNA Damage Induced by Ionizing Radiation

10.20944/preprints202011.0339.v2 ◽

2020 ◽

Author(s):

Kalaiyarasi Ragunathan ◽

Nikki Lyn Esnardo Upfold ◽

Valentyn Oksenych

Keyword(s):

Dna Damage ◽

Tumor Microenvironment ◽

Ionizing Radiation ◽

Immune Cells ◽

Mammalian Cells ◽

Cancer Associated Fibroblasts ◽

Cell Type ◽

Dna Damages ◽

Damage Response ◽

High Doses

Cancer-associated fibroblasts (CAF) form the basis of tumor microenvironment and possess immunomodulatory functions by interacting with other cells surrounding tumor, including T lymphocytes, macrophages, dendritic cells and natural killer cells. Ionizing radiation is a broadly-used method in radiotherapy to target tumors. In mammalian cells, ionizing radiation induces various types of DNA damages and DNA damage response. Being unspecific, radiotherapy affects all the cells in tumor microenvironment, including the tumor itself, CAFs and immune cells. CAFs are extremely radio-resistant and do not initiate apoptosis even at high doses of radiation. However, following radiation, CAFs become senescent and produce a distinct combination of immunoregulatory molecules. Radiosensitivity of immune cells varies depending on the cell type due to inefficient DNA repair in, for example, monocytes and granulocytes. In this minireview, we are summarizing recent findings on the interaction between CAF, ionizing radiation and immune cells in the tumor microenvironment.

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