ABSTRACT
Neutrophils are the most abundant leukocytes in human blood and play a primary role in resistance against invading microorganisms and in the acute inflammatory response. However, their role in colitis and colitis-associated colorectal cancer is still under debate. This study aims to dissect the role of neutrophils in these pathologic contexts by using a rigorous genetic approach. Neutrophil-deficient mice (Csf3r-/- mice) were used in classic models of colitis and colitis-associated colorectal cancer and the role of neutrophils was assessed by histologic, cellular, and molecular analyses coupled with adoptive cell transfer. We also performed correlative analyses using human datasets. Csf3r-/- mice showed increased susceptibility to colitis and colitis-associated colorectal cancer compared with control Csf3r+/+ mice and adoptive transfer of neutrophils in Csf3r-/- mice reverted the phenotype. In colitis, Csf3r-/- mice showed increased bacterial invasion and a reduced number of healing ulcers in the colon, indicating a compromised regenerative capacity of epithelial cells. Neutrophils were essential for γδ T-cell polarization and IL22 production. In patients with ulcerative colitis, expression of CSF3R was positively correlated with IL22 and IL23 expression. Moreover, gene signatures associated with epithelial-cell development, proliferation, and antimicrobial response were enriched in CSF3Rhigh patients. Our data support a model where neutrophils mediate protection against intestinal inflammation and colitis-associated colorectal cancer by controlling the intestinal microbiota and driving the activation of an IL22-dependent tissue repair pathway.
Subject(s)
Colitis, Ulcerative , Colitis-Associated Neoplasms , Neutrophils , Animals , Humans , Mice , Carcinogenesis , Colitis/pathology , Colitis, Ulcerative/metabolism , Colitis-Associated Neoplasms/pathology , Disease Models, Animal , Mice, Inbred C57BL , Mice, Knockout , Neutrophils/immunology , Neutrophils/metabolismABSTRACT
Neutrophils are the most abundant circulating leukocytes in humans and the first immune cells recruited at the site of inflammation. Classically perceived as short-lived effector cells with limited plasticity and diversity, neutrophils are now recognized as highly heterogenous immune cells, which can adapt to various environmental cues. In addition to playing a central role in the host defence, neutrophils are involved in pathological contexts such as inflammatory diseases and cancer. The prevalence of neutrophils in these conditions is usually associated with detrimental inflammatory responses and poor clinical outcomes. However, a beneficial role for neutrophils is emerging in several pathological contexts, including in cancer. Here we will review the current knowledge of neutrophil biology and heterogeneity in steady state and during inflammation, with a focus on the opposing roles of neutrophils in different pathological contexts.
Subject(s)
Neoplasms , Neutrophils , Humans , Inflammation , Leukocytes/pathologyABSTRACT
In metabolic conditions such as obesity and diabetes, which are associated with deregulated signaling of the insulin/insulin-like growth factor system (IIGFs), inflammation plays a dominant role. In cancer, IIGFs is implicated in disease progression, particularly during obesity and diabetes; however, further mediators may act in concert with IIGFs to trigger meta-inflammation. The receptor for advanced glycation end-products (RAGE) and its ligands bridge together metabolism and inflammation in obesity, diabetes, and cancer. Herein, we summarize the main mechanisms of meta-inflammation in malignancies associated with obesity and diabetes; we provide our readers with the most recent understanding and conceptual advances on the role of RAGE at the crossroad between impaired metabolism and inflammation, toward disease aggressiveness. We inform on the potential hubs of cross-communications driven by aberrant RAGE axis and dysfunctional IIGFs in the tumor microenvironment. Furthermore, we offer a rationalized view on the opportunity to terminate meta-inflammation via targeting RAGE pathway, and on the possibility to shut its molecular connections with IIGFs, toward a better control of diabetes- and obesity-associated cancers.
Subject(s)
Neoplasms , Somatomedins , Humans , Glycation End Products, Advanced/metabolism , Inflammation/metabolism , Insulin , Neoplasms/metabolism , Obesity/metabolism , Receptor for Advanced Glycation End Products/metabolism , Tumor MicroenvironmentABSTRACT
Liver cancer represents the fourth leading cause of cancer-associated death worldwide. The heterogeneity of its tumor microenvironment (TME) is a major contributing factor of metastasis, relapse, and drug resistance. Regrettably, late diagnosis makes most liver cancer patients ineligible for surgery, and the frequent failure of non-surgical therapeutic options orientates clinical research to the investigation of new drugs. In this context, cellular senescence has been recently shown to play a pivotal role in the progression of chronic inflammatory liver diseases, ultimately leading to cancer. Moreover, the stem-like state triggered by senescence has been associated with the emergence of drug-resistant, aggressive tumor clones. In recent years, an increasing number of studies have emerged to investigate senescence-associated hepatocarcinogenesis and its derived therapies, leading to promising results. In this review, we intend to provide an overview of the recent evidence that unveils the role of cellular senescence in the most frequent forms of primary and metastatic liver cancer, focusing on the involvement of this mechanism in therapy resistance.
ABSTRACT
HCC, the most prevalent form of primary liver cancer, is prototypically an inflammation-driven cancer developing after years of inflammatory insults. Consequently, the hepatic microenvironment is a site of complex immunological activities. Moreover, the tolerogenic nature of the liver can act as a barrier to anti-tumor immunity, fostering cancer progression and resistance to immunotherapies based on immune checkpoint inhibitors (ICB). In addition to being a site of primary carcinogenesis, many cancer types have high tropism for the liver, and patients diagnosed with liver metastasis have a dismal prognosis. Therefore, understanding the immunological networks characterizing the tumor microenvironment (TME) of HCC will deepen our understanding of liver immunity, and it will underpin the dominant mechanisms controlling both spontaneous and therapy-induced anti-tumor immune responses. Herein, we discuss the contributions of the cellular and molecular components of the liver immune contexture during HCC onset and progression by underscoring how the balance between antagonistic immune responses can recast the properties of the TME and the response to ICB.
ABSTRACT
Type I interferons (IFN-Is) are prototypical inflammatory cytokines produced in response to stress. IFN-Is have a critical role in antitumor immunity by driving the activation of leukocytes and favoring the elimination of malignant cells. However, IFN-I signaling in cancer, specifically in the tumor microenvironment (TME), can have opposing roles. Sustained IFN-I stimulation can promote immune exhaustion or enable tumor cell-intrinsic malignant features. Herein, we discuss the potential impact of the insulin/insulin-like growth factor system (I/IGFs) and of metabolic disorders in aberrant IFN-I signaling in cancer. We consider the possibility that targeting I/IGFs, especially in patients with cancer affected by metabolic disorders, contributes to an effective strategy to inhibit deleterious IFN-I signaling, thereby restoring sensitivity to various cancer therapies, including immunotherapy.
Subject(s)
Insulin , Neoplasms , Humans , Insulin/metabolism , Insulin-Like Growth Factor I/metabolism , Neoplasms/metabolism , Signal Transduction , Tumor MicroenvironmentABSTRACT
Cytotoxic therapies, besides directly inducing cancer cell death, can stimulate immune-dependent tumor growth control or paradoxically accelerate tumor progression. The underlying mechanisms dictating these opposing outcomes are poorly defined. Here, we show that cytotoxic therapy acutely upregulates cyclooxygenase (COX)-2 expression and prostaglandin E2 (PGE2) production in cancer cells with pre-existing COX-2 activity. Screening a compound library of 1280 approved drugs, we find that all classes of chemotherapy drugs enhance COX-2 transcription whilst arresting cancer cell proliferation. Genetic manipulation of COX-2 expression or its gene promoter region uncover how augmented COX-2/PGE2 activity post-treatment profoundly alters the inflammatory properties of chemotherapy-treated cancer cells in vivo. Pharmacological COX-2 inhibition boosts the efficacy of the combination of chemotherapy and PD-1 blockade. Crucially, in a poorly immunogenic breast cancer model, only the triple therapy unleashes tumor growth control and significantly reduces relapse and spontaneous metastatic spread in an adjuvant setting. Our findings suggest COX-2/PGE2 upregulation by dying cancer cells acts as a major barrier to cytotoxic therapy-driven tumor immunity and uncover a strategy to improve the outcomes of immunotherapy and chemotherapy combinations.
Subject(s)
Antineoplastic Agents , Neoplasms , Antineoplastic Agents/pharmacology , Cyclooxygenase 2/genetics , Cyclooxygenase 2/metabolism , Dinoprostone/metabolism , Immunotherapy , Up-RegulationABSTRACT
Identifying strategies to improve the efficacy of immune checkpoint blockade (ICB) remains a major clinical need. Here, we show that therapeutically targeting the COX2/PGE2/EP2-4 pathway with widely used nonsteroidal and steroidal anti-inflammatory drugs synergized with ICB in mouse cancer models. We exploited a bilateral surgery model to distinguish responders from nonresponders shortly after treatment and identified acute IFNγ-driven transcriptional remodeling in responder mice, which was also associated with patient benefit to ICB. Monotherapy with COX2 inhibitors or EP2-4 PGE2 receptor antagonists rapidly induced this response program and, in combination with ICB, increased the intratumoral accumulation of effector T cells. Treatment of patient-derived tumor fragments from multiple cancer types revealed a similar shift in the tumor inflammatory environment to favor T-cell activation. Our findings establish the COX2/PGE2/EP2-4 axis as an independent immune checkpoint and a readily translatable strategy to rapidly switch the tumor inflammatory profile from cold to hot. SIGNIFICANCE: Through performing in-depth profiling of mice and human tumors, this study identifies mechanisms by which anti-inflammatory drugs rapidly alter the tumor immune landscape to enhance tumor immunogenicity and responses to immune checkpoint inhibitors.See related commentary by Melero et al., p. 2372.This article is highlighted in the In This Issue feature, p. 2355.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Immune Checkpoint Inhibitors/therapeutic use , Neoplasms/drug therapy , Animals , Anti-Inflammatory Agents/administration & dosage , Cell Line, Tumor , Disease Models, Animal , Drug Therapy, Combination , Humans , Immune Checkpoint Inhibitors/administration & dosage , Mice , Tumor MicroenvironmentABSTRACT
Inflammation can support or restrain cancer progression and the response to therapy. Here, we searched for primary regulators of cancer-inhibitory inflammation through deep profiling of inflammatory tumor microenvironments (TMEs) linked to immune-dependent control in mice. We found that early intratumoral accumulation of interferon gamma (IFN-γ)-producing natural killer (NK) cells induced a profound remodeling of the TME and unleashed cytotoxic T cell (CTL)-mediated tumor eradication. Mechanistically, tumor-derived prostaglandin E2 (PGE2) acted selectively on EP2 and EP4 receptors on NK cells, hampered the TME switch, and enabled immune evasion. Analysis of patient datasets across human cancers revealed distinct inflammatory TME phenotypes resembling those associated with cancer immune control versus escape in mice. This allowed us to generate a gene-expression signature that integrated opposing inflammatory factors and predicted patient survival and response to immune checkpoint blockade. Our findings identify features of the tumor inflammatory milieu associated with immune control of cancer and establish a strategy to predict immunotherapy outcomes.
Subject(s)
Immune Checkpoint Inhibitors/therapeutic use , Inflammation/immunology , Neoplasms/immunology , Tumor Escape/immunology , Animals , Dinoprostone/metabolism , Humans , Immunotherapy , Inflammation/genetics , Interferon-gamma/metabolism , Killer Cells, Natural/immunology , Mice , Neoplasms/therapy , Phenotype , Prognosis , Prostaglandin-Endoperoxide Synthases/genetics , Receptors, Prostaglandin E, EP2 Subtype/metabolism , Receptors, Prostaglandin E, EP4 Subtype/metabolism , T-Lymphocytes, Cytotoxic/immunology , Tumor Microenvironment/immunologyABSTRACT
Neutrophils are a component of the tumor microenvironment and have been predominantly associated with cancer progression. Using a genetic approach complemented by adoptive transfer, we found that neutrophils are essential for resistance against primary 3-methylcholantrene-induced carcinogenesis. Neutrophils were essential for the activation of an interferon-γ-dependent pathway of immune resistance, associated with polarization of a subset of CD4- CD8- unconventional αß T cells (UTCαß). Bulk and single-cell RNA sequencing (scRNA-seq) analyses unveiled the innate-like features and diversity of UTCαß associated with neutrophil-dependent anti-sarcoma immunity. In selected human tumors, including undifferentiated pleomorphic sarcoma, CSF3R expression, a neutrophil signature and neutrophil infiltration were associated with a type 1 immune response and better clinical outcome. Thus, neutrophils driving UTCαß polarization and type 1 immunity are essential for resistance against murine sarcomas and selected human tumors.
Subject(s)
Disease Resistance , Neoplasms/pathology , Neutrophils/immunology , Sarcoma/pathology , T-Lymphocytes/metabolism , Animals , Chromones/toxicity , Disease Resistance/immunology , Humans , Immunity, Innate , Interferon-gamma/genetics , Interferon-gamma/metabolism , Interleukin-12/genetics , Interleukin-12/metabolism , Kaplan-Meier Estimate , Macrophages/immunology , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neoplasms/immunology , Neoplasms/mortality , Neutrophil Infiltration , Neutrophils/cytology , Neutrophils/metabolism , Receptors, Colony-Stimulating Factor/metabolism , Sarcoma/chemically induced , Sarcoma/immunology , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Tumor MicroenvironmentABSTRACT
AIMS: Low-grade chronic inflammation characterizes obesity and metabolic syndrome. Here, we aim at investigating the impact of the acute-phase protein long pentraxin 3 (PTX3) on the immune-inflammatory response occurring during diet-induced obesity. METHODS AND RESULTS: PTX3 deficiency in mice fed a high-fat diet for 20 weeks protects from weight gain and adipose tissue deposition in visceral and subcutaneous depots. This effect is not related to changes in glucose homeostasis and lipid metabolism but is associated with an improved immune cell phenotype in the adipose tissue of Ptx3 deficient animals, which is characterized by M2-macrophages polarization and increased angiogenesis. These findings are recapitulated in humans where carriers of a PTX3 haplotype (PTX3 h2/h2 haplotype), resulting in lower PTX3 plasma levels, presented with a reduced prevalence of obesity and decreased abdominal adiposity compared with non-carriers. CONCLUSION: Our results support a critical role for PTX3 in the onset of obesity by promoting inflammation and limiting adipose tissue vascularization and delineate PTX3 targeting as a valuable strategy for the treatment of adipose tissue-associated inflammatory response.
Subject(s)
C-Reactive Protein/deficiency , Diet, High-Fat , Energy Metabolism , Immunity, Innate , Inflammation Mediators/metabolism , Inflammation/prevention & control , Intra-Abdominal Fat/blood supply , Intra-Abdominal Fat/metabolism , Nerve Tissue Proteins/deficiency , Obesity/metabolism , Subcutaneous Fat/blood supply , Subcutaneous Fat/metabolism , Adipogenesis , Adiposity , Aged , Animals , C-Reactive Protein/genetics , Cell Plasticity , Cells, Cultured , Disease Models, Animal , Female , Haplotypes , Humans , Inflammation/immunology , Inflammation/metabolism , Inflammation/physiopathology , Inflammation Mediators/immunology , Intra-Abdominal Fat/immunology , Macrophages/immunology , Macrophages/metabolism , Male , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Neovascularization, Physiologic , Nerve Tissue Proteins/genetics , Obesity/immunology , Obesity/physiopathology , Obesity, Abdominal/epidemiology , Obesity, Abdominal/genetics , Obesity, Abdominal/physiopathology , Phenotype , Serum Amyloid P-Component/genetics , Signal Transduction , Subcutaneous Fat/immunology , Weight GainABSTRACT
Conventional type 1 dendritic cells (cDC1) are critical for antitumor immunity, and their abundance within tumors is associated with immune-mediated rejection and the success of immunotherapy. Here, we show that cDC1 accumulation in mouse tumors often depends on natural killer (NK) cells that produce the cDC1 chemoattractants CCL5 and XCL1. Similarly, in human cancers, intratumoral CCL5, XCL1, and XCL2 transcripts closely correlate with gene signatures of both NK cells and cDC1 and are associated with increased overall patient survival. Notably, tumor production of prostaglandin E2 (PGE2) leads to evasion of the NK cell-cDC1 axis in part by impairing NK cell viability and chemokine production, as well as by causing downregulation of chemokine receptor expression in cDC1. Our findings reveal a cellular and molecular checkpoint for intratumoral cDC1 recruitment that is targeted by tumor-derived PGE2 for immune evasion and that could be exploited for cancer therapy.
Subject(s)
Dendritic Cells/immunology , Killer Cells, Natural/immunology , Neoplasms/immunology , Neoplasms/pathology , Tumor Microenvironment/immunology , Animals , Cell Line, Tumor , Chemokine CCL5/metabolism , Chemokines, C/metabolism , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/metabolism , Dinoprostone/metabolism , Gene Expression Regulation, Neoplastic , Humans , Melanoma/genetics , Melanoma/pathology , Mice , Mutation/genetics , Prognosis , Proto-Oncogene Proteins B-raf/genetics , Survival AnalysisABSTRACT
In this issue of JEM, Sulciner et al. (https://doi.org/10.1084/jem.20170681) provide evidence that therapy-induced cancer cell death can, paradoxically, stimulate and accelerate the growth of surviving malignant cells by fueling tumor-promoting inflammation. Resolvins, a class of lipid mediators, counteract this effect, representing an attractive target for therapeutic intervention.
Subject(s)
Cell Death , Neoplasms , Cell Count , Fatty Acids , Humans , InflammationABSTRACT
Interleukin-1 receptor 8 (IL-1R8, also known as single immunoglobulin IL-1R-related receptor, SIGIRR, or TIR8) is a member of the IL-1 receptor (ILR) family with distinct structural and functional characteristics, acting as a negative regulator of ILR and Toll-like receptor (TLR) downstream signalling pathways and inflammation. Natural killer (NK) cells are innate lymphoid cells which mediate resistance against pathogens and contribute to the activation and orientation of adaptive immune responses. NK cells mediate resistance against haematopoietic neoplasms but are generally considered to play a minor role in solid tumour carcinogenesis. Here we report that IL-1R8 serves as a checkpoint for NK cell maturation and effector function. Its genetic blockade unleashes NK-cell-mediated resistance to hepatic carcinogenesis, haematogenous liver and lung metastasis, and cytomegalovirus infection.
Subject(s)
Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Liver Neoplasms/immunology , Muromegalovirus/immunology , Receptors, Interleukin-1/immunology , Animals , Cell Differentiation/genetics , Female , Herpesviridae Infections/genetics , Herpesviridae Infections/immunology , Humans , Killer Cells, Natural/metabolism , Liver Neoplasms/genetics , Lymphocyte Activation/genetics , Male , Mice , Mice, Inbred C57BL , Neoplasm Metastasis/genetics , Neoplasm Metastasis/immunology , Receptors, Interleukin-1/geneticsABSTRACT
Inflammatory cells are an essential component of the tumor microenvironment. Neutrophils have emerged as important players in the orchestration and effector phase of innate and adaptive immunity. The significance of tumor-associated neutrophils (TAN) in colorectal cancer (CRC) has been the subject of conflicting reports and the present study was designed to set up a reliable methodology to assess TAN infiltration in CRC and to evaluate their clinical significance. CD66b and myeloperoxidase (MPO) were assessed as candidate neutrophil markers in CRC using immunohistochemistry. CD66b was found to be a reliable marker to identify TAN in CRC tissues, whereas MPO also identified a subset of CD68(+) macrophages. CRC patients (n = 271) (Stages I-IV) were investigated retrospectively by computer-assisted imaging on whole tumor sections. TAN density dramatically decreases in Stage IV patients as compared to Stage I-III. At Cox analysis, higher TAN density was associated with better prognosis. Importantly, multivariate analysis showed that prognostic significance of TAN can be influenced by clinical stage and 5-fluorouracil(5-FU)-based chemotherapy. On separate analysis of Stage III patients (n = 178), TAN density had a dual clinical significance depending on the use of 5-FU-based chemotherapy. Unexpectedly, higher TAN density was associated with better response to 5-FU-based chemotherapy. Thus, TAN are an important component of the immune cell infiltrate in CRC and assessment of TAN infiltration may help identify patients likely to benefit from 5-FU-based chemotherapy. These results call for a reassessment of the role of neutrophils in cancer using rigorous quantitative methodology.
Subject(s)
Colorectal Neoplasms/pathology , Neutrophil Infiltration , Neutrophils/pathology , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/mortality , Disease Progression , Female , Humans , Male , Microsatellite Repeats , Middle Aged , Neoplasm Staging , Neutrophils/metabolism , Prognosis , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Survival AnalysisABSTRACT
The innate immune system represents the first line of defense against pathogens and comprises both a cellular and a humoral arm. Fluid-phase pattern recognition molecules (PRMs), which include collectins, ficolins, and pentraxins, are key components of the humoral arm of innate immunity and are expressed by a variety of cells, including myeloid, epithelial, and endothelial cells, mainly in response to infectious and inflammatory conditions. Soluble PRMs share basic multifunctional properties including activation and regulation of the complement cascade, opsonization of pathogens and apoptotic cells, regulation of leukocyte extravasation, and fine-tuning of inflammation. Therefore, soluble PRMs are part of the immune response and retain antibody-like effector functions. Here, we will review the expression and general function of soluble PRMs, focusing our attention on the long pentraxin PTX3.
Subject(s)
C-Reactive Protein/metabolism , Immunity, Humoral , Immunity, Innate , Lectins/metabolism , Myeloid Cells/immunology , Animals , HumansSubject(s)
C-Reactive Protein/immunology , Inflammation/immunology , Neoplasms/immunology , Serum Amyloid P-Component/immunology , Tumor Suppressor Proteins/immunology , C-Reactive Protein/genetics , C-Reactive Protein/metabolism , Complement System Proteins/immunology , Epigenesis, Genetic/immunology , Humans , Immunity, Humoral/genetics , Immunity, Humoral/immunology , Immunity, Innate/genetics , Immunity, Innate/immunology , Inflammation/genetics , Inflammation/metabolism , Models, Immunological , Neoplasms/genetics , Neoplasms/metabolism , Serum Amyloid P-Component/genetics , Serum Amyloid P-Component/metabolism , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolismABSTRACT
Inflammation is a key component of the tumor microenvironment. Tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) are prototypic inflammatory cells in cancer-related inflammation. Macrophages provide a first line of resistance against infectious agents but in the ecological niche of cancer behave as corrupted policemen. TAMs promote tumor growth and metastasis by direct interactions with cancer cells, including cancer stem cells, as well as by promoting angiogenesis and tissue remodeling and suppressing effective adaptive immunity. In addition, the efficacy of chemotherapy, radiotherapy, and checkpoint blockade inhibitors is profoundly affected by regulation of TAMs. In particular, TAMs can protect and rescue tumor cells from cytotoxic therapy by orchestrating a misguided tissue repair response. Following extensive preclinical studies, there is now proof of concept that targeting tumor-promoting macrophages by diverse strategies (e.g., Trabectedin, anti-colony-stimulating factor-1 receptor antibodies) can result in antitumor activity in human cancer and further studies are ongoing. Neutrophils have long been overlooked as a minor component of the tumor microenvironment, but there is evidence for an important role of TANs in tumor progression. Targeting phagocytes (TAMs and TANs) as corrupted policemen in cancer may pave the way to innovative therapeutic strategies complementing cytoreductive therapies and immunotherapy.
Subject(s)
Inflammation/immunology , Macrophages/immunology , Neoplasms/immunology , Neoplasms/pathology , Phagocytes/pathology , Tumor Microenvironment/immunology , Animals , Humans , Phagocytes/immunologyABSTRACT
PTX3 is an essential component of the humoral arm of innate immunity, playing a nonredundant role in resistance against selected microbes and in the regulation of inflammation. PTX3 activates and regulates the Complement cascade by interacting with C1q and with Factor H. PTX3 deficiency was associated with increased susceptibility to mesenchymal and epithelial carcinogenesis. Increased susceptibility of Ptx3(-/-) mice was associated with enhanced macrophage infiltration, cytokine production, angiogenesis, and Trp53 mutations. Correlative evidence, gene-targeted mice, and pharmacological blocking experiments indicated that PTX3 deficiency resulted in amplification of Complement activation, CCL2 production, and tumor-promoting macrophage recruitment. PTX3 expression was epigenetically regulated in selected human tumors (e.g., leiomyosarcomas and colorectal cancer) by methylation of the promoter region and of a putative enhancer. Thus, PTX3, an effector molecule belonging to the humoral arm of innate immunity, acts as an extrinsic oncosuppressor gene in mouse and man by regulating Complement-dependent, macrophage-sustained, tumor-promoting inflammation.
Subject(s)
C-Reactive Protein/genetics , C-Reactive Protein/metabolism , Inflammation/metabolism , Neoplasms/immunology , Serum Amyloid P-Component/genetics , Serum Amyloid P-Component/metabolism , Animals , Complement System Proteins/metabolism , DNA Methylation , Genes, p53 , Humans , Mice , MutationABSTRACT
The innate immune system is composed of a cellular arm and a humoral arm. Components of the humoral arm include members of the complement cascade and soluble pattern recognition molecules (PRMs). These PRMs recognize pathogen-associated molecular patterns and are functional ancestors of antibodies, playing a role in complement activation, opsonization and agglutination. Pentraxins consist of a set of multimeric soluble proteins and represent the prototypic components of humoral innate immunity. The prototypic long pentraxin PTX3 is highly conserved in evolution and produced by somatic and innate immune cells after proinflammatory stimuli. PTX3 interacts with a set of self, nonself and modified self ligands and exerts essential roles in innate immunity, inflammation control and matrix deposition. In addition, translational studies suggest that PTX3 may be a useful biomarker of human pathologies complementary to C-reactive protein. In this study, we will review the general functions of pentraxins in innate immunity and inflammation, focusing our attention on the prototypic long pentraxin PTX3.