Mesenchymal Stem Cell: A Friend or Foe in Anti-Tumor Immunity

Mesenchymal stem cells (MSCs) are self-renewable, multipotent stem cells that regulate the phenotype and function of all immune cells that participate in anti-tumor immunity. MSCs modulate the antigen-presenting properties of dendritic cells, affect chemokine and cytokine production in macrophages and CD4+ T helper cells, alter the cytotoxicity of CD8+ T lymphocytes and natural killer cells and regulate the generation and expansion of myeloid-derived suppressor cells and T regulatory cells. As plastic cells, MSCs adopt their phenotype and function according to the cytokine profile of neighboring tumor-infiltrated immune cells. Depending on the tumor microenvironment to which they are exposed, MSCs may obtain pro- and anti-tumorigenic phenotypes and may enhance or suppress tumor growth. Due to their tumor-homing properties, MSCs and their exosomes may be used as vehicles for delivering anti-tumorigenic agents in tumor cells, attenuating their viability and invasive characteristics. Since many factors affect the phenotype and function of MSCs in the tumor microenvironment, a better understanding of signaling pathways that regulate the cross-talk between MSCs, immune cells and tumor cells will pave the way for the clinical use of MSCs in cancer immunotherapy. In this review article, we summarize current knowledge on the molecular and cellular mechanisms that are responsible for the MSC-dependent modulation of the anti-tumor immune response and we discuss different insights regarding therapeutic potential of MSCs in the therapy of malignant diseases.

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The Cross-Talk between Mesenchymal Stem Cells and Immune Cells in Tissue Repair and Regeneration

International Journal of Molecular Sciences ◽

10.3390/ijms22052472 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2472

Author(s):

Carl Randall Harrell ◽

Valentin Djonov ◽

Vladislav Volarevic

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Immune Cells ◽

Tissue Repair ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Multipotent Stem Cells ◽

Tissue Repair And Regeneration ◽

Almost All ◽

And Function

Mesenchymal stem cells (MSCs) are self-renewable, rapidly proliferating, multipotent stem cells which reside in almost all post-natal tissues. MSCs possess potent immunoregulatory properties and, in juxtacrine and paracrine manner, modulate phenotype and function of all immune cells that participate in tissue repair and regeneration. Additionally, MSCs produce various pro-angiogenic factors and promote neo-vascularization in healing tissues, contributing to their enhanced repair and regeneration. In this review article, we summarized current knowledge about molecular mechanisms that regulate the crosstalk between MSCs and immune cells in tissue repair and regeneration.

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Siglec Signaling in the Tumor Microenvironment

Frontiers in Immunology ◽

10.3389/fimmu.2021.790317 ◽

2021 ◽

Vol 12 ◽

Author(s):

Eline J. H. van Houtum ◽

Christian Büll ◽

Lenneke A. M. Cornelissen ◽

Gosse J. Adema

Keyword(s):

Sialic Acid ◽

Tumor Microenvironment ◽

Immune Cells ◽

Current Knowledge ◽

Surface Distribution ◽

Tumor Immune Evasion ◽

Binding Preference ◽

Ligand Expression ◽

And Function ◽

Tumor Types

Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of receptors that recognize sialoglycans – sialic acid containing glycans that are abundantly present on cell membranes. Siglecs are expressed on most immune cells and can modulate their activity and function. The majority of Siglecs contains immune inhibitory motifs comparable to the immune checkpoint receptor PD-1. In the tumor microenvironment (TME), signaling through the Siglec-sialoglycan axis appears to be enhanced through multiple mechanisms favoring tumor immune evasion similar to the PD-1/PD-L1 signaling pathway. Siglec expression on tumor-infiltrating immune cells appears increased in the immune suppressive microenvironment. At the same time, enhanced Siglec ligand expression has been reported for several tumor types as a result of aberrant glycosylation, glycan modifications, and the increased expression of sialoglycans on proteins and lipids. Siglec signaling has been identified as important regulator of anti-tumor immunity in the TME, but the key factors contributing to Siglec activation by tumor-associated sialoglycans are diverse and poorly defined. Among others, Siglec activation and signaling are co-determined by their expression levels, cell surface distribution, and their binding preferences for cis- and trans-ligands in the TME. Siglec binding preference are co-determined by the nature of the proteins/lipids to which the sialoglycans are attached and the multivalency of the interaction. Here, we review the current understanding and emerging conditions and factors involved in Siglec signaling in the TME and identify current knowledge gaps that exist in the field.

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Mesenchymal Stem Cells, Immune Cells and Tumor Cells Crosstalk: A Sinister Triangle in the Tumor Microenvironment

Current Stem Cell Research & Therapy ◽

10.2174/1574888x13666180816114809 ◽

2019 ◽

Vol 14 (1) ◽

pp. 43-51 ◽

Cited By ~ 3

Author(s):

Mahboobeh Razmkhah ◽

Shabnam Abtahi ◽

Abbas Ghaderi

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Microenvironment ◽

Immune Responses ◽

Tumor Cells ◽

Immune Cells ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Adaptive Immune ◽

Adaptive Immune Cells

Mesenchymal Stem Cells [MSCs] are a heterogeneous population of fibroblast-like cells which maintain self-renewability and pluripotency. Many studies have demonstrated the immunomodulatory effects of MSCs on the innate and adaptive immune cells. As a result of interactions with tumor cells, microenvironment and immune-stimulating milieu, MSCs contribute to tumor progression by several mechanisms, including sustained proliferative signal in cancer stem cells [CSCs], inhibition of tumor cell apoptosis, transition to tumor-associated fibroblasts [TAFs], promotion of angiogenesis, stimulation of epithelial-mesenchymal transition [EMT], suppression of immune responses, and consequential promotion of tumor metastasis. Here, we present an overview of the latest findings on Janusfaced roles that MSCs play in the tumor microenvironment [TME], with a concise focus on innate and adaptive immune responses.

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Neutrophil in the Pancreatic Tumor Microenvironment

Biomolecules ◽

10.3390/biom11081170 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1170

Author(s):

Lin Jin ◽

Hong Sun Kim ◽

Jiaqi Shi

Keyword(s):

Tumor Microenvironment ◽

Tumor Cells ◽

Immune Cells ◽

Poor Prognosis ◽

Pancreatic Tumor ◽

Survival Rates ◽

Ductal Adenocarcinoma ◽

Cellular Mechanisms ◽

Therapeutic Implications ◽

Tumor Lesion

Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a poor prognosis and low survival rates. PDAC is characterized by a fibroinflammatory tumor microenvironment enriched by abundant fibroblasts and a variety of immune cells, contributing to its aggressiveness. Neutrophils are essential infiltrating immune cells in the PDAC microenvironment. Recent studies have identified several cellular mechanisms by which neutrophils are recruited to tumor lesion and promote tumorigenesis. This review summarizes the current understanding of the interplay between neutrophils, tumor cells, and other components in the PDAC tumor microenvironment. The prognosis and therapeutic implications of neutrophils in PDAC are also discussed.

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The CC and CXC chemokines: major regulators of tumor progression and the tumor microenvironment

AJP Cell Physiology ◽

10.1152/ajpcell.00378.2019 ◽

2020 ◽

Vol 318 (3) ◽

pp. C542-C554 ◽

Cited By ~ 3

Author(s):

Andreas Bikfalvi ◽

Clotilde Billottet

Keyword(s):

Cell Proliferation ◽

Tumor Microenvironment ◽

Tumor Progression ◽

Tumor Cells ◽

Tumor Immunity ◽

Chemokine Receptor ◽

Immune Cells ◽

Immune Dysfunction ◽

Mechanisms Of Action ◽

Migration Of Cells

Chemokines are a family of soluble cytokines that act as chemoattractants to guide the migration of cells, in particular of immune cells. However, chemokines are also involved in cell proliferation, differentiation, and survival. Chemokines are associated with a variety of human diseases including chronic inflammation, immune dysfunction, cancer, and metastasis. This review discusses the expression of CC and CXC chemokines in the tumor microenvironment and their supportive and inhibitory roles in tumor progression, angiogenesis, metastasis, and tumor immunity. We also specially focus on the diverse roles of CXC chemokines (CXCL9–11, CXCL4 and its variant CXCL4L1) and their two chemokine receptor CXCR3 isoforms, CXCR3-A and CXCR3-B. These two distinct isoforms have divergent roles in tumors, either promoting (CXCR3-A) or inhibiting (CXCR3-B) tumor progression. Their effects are mediated not only directly in tumor cells but also indirectly via the regulation of angiogenesis and tumor immunity. A full comprehension of their mechanisms of action is critical to further validate these chemokines and their receptors as biomarkers or therapeutic targets in cancer.

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Therapeutic Potential of Mesenchymal Stem Cells and Their Secretome in the Treatment of Glaucoma

Stem Cells International ◽

10.1155/2019/7869130 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

C. Randall Harrell ◽

Crissy Fellabaum ◽

Aleksandar Arsenijevic ◽

Bojana Simovic Markovic ◽

Valentin Djonov ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Visual Information ◽

Therapeutic Potential ◽

Current Knowledge ◽

Therapeutic Agents ◽

Dependent Manner ◽

Cellular Mechanisms ◽

Cell Based Therapy ◽

Glaucoma Treatment

Glaucoma represents a group of progressive optic neuropathies characterized by gradual loss of retinal ganglion cells (RGCs), the neurons that conduct visual information from the retina to the brain. Elevated intraocular pressure (IOP) is considered the main reason for enhanced apoptosis of RGCs in glaucoma. Currently used therapeutic agents are not able to repopulate and/or regenerate injured RGCs and, therefore, are ineffective in most patients with advanced glaucoma. Accordingly, several new therapeutic approaches, including stem cell-based therapy, have been explored for the glaucoma treatment. In this review article, we emphasized current knowledge regarding molecular and cellular mechanisms responsible for beneficial effects of mesenchymal stem cells (MSCs) and their secretome in the treatment of glaucoma. MSCs produce neurotrophins and in an exosome-dependent manner supply injured RGCs with growth factors enhancing their survival and regeneration. Additionally, MSCs are able to generate functional RGC-like cells and induce proliferation of retinal stem cells. By supporting integrity of trabecular meshwork, transplanted MSCs alleviate IOP resulting in reduced loss of RGCs. Moreover, MSCs are able to attenuate T cell-driven retinal inflammation providing protection to the injured retinal tissue. In summing up, due to their capacity for neuroprotection and immunomodulation, MSCs and their secretome could be explored in upcoming clinical studies as new therapeutic agents for glaucoma treatment.

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Knockout of High-Mobility Group Box 1 in B16F10 Melanoma Cells Induced Host Immunity-Mediated Suppression of In Vivo Tumor Growth

10.21203/rs.3.rs-1187786/v1 ◽

2021 ◽

Author(s):

Kanako Yokomizo ◽

Kayoko Waki ◽

Miyako Ozawa ◽

Keiko Yamamoto ◽

Sachiko Ogasawara ◽

...

Keyword(s):

T Cells ◽

Tumor Microenvironment ◽

Tumor Growth ◽

Tumor Cells ◽

Tumor Immunity ◽

Cd8 T Cells ◽

Immune Cells ◽

High Mobility

Abstract High mobility group box 1 (HMGB1) has been reported as a damage-associated molecular pattern (DAMP) molecule that is released from damaged or dead cells and induces inflammation and subsequent innate immunity. However, the role of HMGB1 in the anti-tumor immunity is unclear since inflammation in the tumor microenvironment also contributes to tumor promotion and progression. In the present study, we established HMGB1-knockout clones from B16F10 and CT26 murine tumors by genome editing using the CRISPR/Cas9 system and investigated the role of HMGB1 in anti-tumor immunity. We found that 1) knockout of HMGB1 in the tumor cells suppressed in vivo, but not in vitro, tumor growth, 2) the suppression of the in vivo tumor growth was mediated by CD8 T cells, and 3) infiltration of CD8 T cells, macrophages and dendritic cells into the tumor tissues was accelerated in HMGB1-knockout tumors. These results demonstrated that knockout of HMGB1 in tumor cells converted tumors from poor infiltration of immune cells called “cold” to “immune-inflamed” or “hot” and inhibited in vivo tumor growth mediated by cytotoxic T lymphocytes. Infiltration of immune cells to the tumor microenvironment is an important step in the series known as the cancer immunity cycle. Thus, manipulation of tumor-derived HMGB1 might be applicable to improve the clinical outcomes of cancer immunotherapies, including immune checkpoint blockades and cancer vaccine therapies.

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Estrogen/ER in anti-tumor immunity regulation to tumor cell and tumor microenvironment

Cancer Cell International ◽

10.1186/s12935-021-02003-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Tiecheng Wang ◽

Jiakang Jin ◽

Chao Qian ◽

Jianan Lou ◽

Jinti Lin ◽

...

Keyword(s):

Tumor Microenvironment ◽

Cancer Immunotherapy ◽

Tumor Immunity ◽

Immune Cells ◽

Target Genes ◽

Target Therapy ◽

Treatment Strategies ◽

Signal Transduction Pathway ◽

Pathway Activation ◽

Immune System Regulation

AbstractAs the essential sexual hormone, estrogen and its receptor has been proved to participate in the regulation of autoimmunity diseases and anti-tumor immunity. The adjustment of tumor immunity is related to the interaction between cancer cells, immune cells and tumor microenvironment, all of which is considered as the potential target in estrogen-induced immune system regulation. However, the specific mechanism of estrogen-induced immunity is poorly understood. Typically, estrogen causes the nuclear localization of estrogen/estrogen receptor complex and alternates the transcription pattern of target genes, leading to the reprogramming of tumor cells and differentiation of immune cells. However, the estrogen-induced non-canonical signal pathway activation is also crucial to the rapid function of estrogen, such as NF-κB, MAPK-ERK, and β-catenin pathway activation, which has not been totally illuminated. So, the investigation of estrogen modulatory mechanisms in these two manners is vital for the tumor immunity and can provide the potential for endocrine hormone targeted cancer immunotherapy. Here, this review summarized the estrogen-induced canonical and non-canonical signal transduction pathway and aimed to focus on the relationship among estrogen and cancer immunity as well as immune-related tumor microenvironment regulation. Results from these preclinical researches elucidated that the estrogen-target therapy has the application prospect of cancer immunotherapy, which requires the further translational research of these treatment strategies.

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The Role of the Bone Marrow Microenvironment in the Response to Infection

Frontiers in Immunology ◽

10.3389/fimmu.2020.585402 ◽

2020 ◽

Vol 11 ◽

Author(s):

Courtney B. Johnson ◽

Jizhou Zhang ◽

Daniel Lucas

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Immune Cells ◽

Critical Role ◽

Primary Source ◽

Bone Marrow Microenvironment ◽

Future Research ◽

Multipotent Stem Cells ◽

Hematopoietic Stem

Hematopoiesis in the bone marrow (BM) is the primary source of immune cells. Hematopoiesis is regulated by a diverse cellular microenvironment that supports stepwise differentiation of multipotent stem cells and progenitors into mature blood cells. Blood cell production is not static and the bone marrow has evolved to sense and respond to infection by rapidly generating immune cells that are quickly released into the circulation to replenish those that are consumed in the periphery. Unfortunately, infection also has deleterious effects injuring hematopoietic stem cells (HSC), inefficient hematopoiesis, and remodeling and destruction of the microenvironment. Despite its central role in immunity, the role of the microenvironment in the response to infection has not been systematically investigated. Here we summarize the key experimental evidence demonstrating a critical role of the bone marrow microenvironment in orchestrating the bone marrow response to infection and discuss areas of future research.

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Hampering Stromal Cells in the Tumor Microenvironment as a Therapeutic Strategy to Destem Cancer Stem Cells

Cancers ◽

10.3390/cancers13133191 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3191

Author(s):

Katherine Po Sin Chung ◽

Rainbow Wing Hei Leung ◽

Terence Kin Wah Lee

Keyword(s):

Stem Cells ◽

Tumor Microenvironment ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Stromal Cells ◽

Current Knowledge ◽

Special Focus ◽

Intrinsic Regulation ◽

Mechanistic Basis ◽

Novel Therapeutic Strategies

Cancer stem cells (CSCs) within the tumor bulk play crucial roles in tumor initiation, recurrence and therapeutic resistance. In addition to intrinsic regulation, a growing body of evidence suggests that the phenotypes of CSCs are also regulated extrinsically by stromal cells in the tumor microenvironment (TME). Here, we discuss the current knowledge of the interplay between stromal cells and cancer cells with a special focus on how stromal cells drive the stemness of cancer cells and immune evasive mechanisms of CSCs. Knowledge gained from the interaction between CSCs and stromal cells will provide a mechanistic basis for the development of novel therapeutic strategies for the treatment of cancers.

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