ABSTRACT
Engineering T cells with chimeric antigen receptors (CARs) has demonstrated remarkable success in eradicating hematological malignancies. In this issue of Immunity, June and colleagues demonstrate the broad antitumor efficacy of a newly-designed CAR targeting the O-linked hypoglycosylated epitopes Tn and sialyl-Tn on cancer-associated MUC-1.
Subject(s)
Neoplasms/immunology , T-Lymphocytes/immunology , Glycosylation , HumansABSTRACT
Galectins, a family of evolutionarily conserved glycan-binding proteins, play key roles in diverse biological processes including tissue repair, adipogenesis, immune cell homeostasis, angiogenesis, and pathogen recognition. Dysregulation of galectins and their ligands has been observed in a wide range of pathologic conditions including cancer, autoimmune inflammation, infection, fibrosis, and metabolic disorders. Through protein-glycan or protein-protein interactions, these endogenous lectins can shape the initiation, perpetuation, and resolution of these processes, suggesting their potential roles in disease monitoring and treatment. However, despite considerable progress, a full understanding of the biology and therapeutic potential of galectins has not been reached due to their diversity, multiplicity of cell targets, and receptor promiscuity. In this article, we discuss the multiple galectin-binding partners present in different cell types, focusing on their contributions to selected physiologic and pathologic settings. Understanding the molecular bases of galectin-ligand interactions, particularly their glycan-dependency, the biochemical nature of selected receptors, and underlying signaling events, might contribute to designing rational therapeutic strategies to control a broad range of pathologic conditions.
Subject(s)
Galectins , Neoplasms , Humans , Galectins/metabolism , Polysaccharides/metabolism , Signal Transduction , Inflammation , LigandsABSTRACT
Colorectal cancer (CRC) represents the third most common malignancy and the second leading cause of cancer-related deaths worldwide. Although immunotherapy has taken center stage in mainstream oncology, it has shown limited clinical efficacy in CRC, generating an urgent need for discovery of new biomarkers and potential therapeutic targets. Galectin-1 (Gal-1), an endogenous glycan-binding protein, induces tolerogenic programs and contributes to tumor cell evasion of immune responses. Here, we investigated the relevance of Gal-1 in CRC and explored its modulatory activity within the CD8+ regulatory T cell (Treg) compartment. Mice lacking Gal-1 (Lgals1-/- ) developed a lower number of tumors and showed a decreased frequency of a particular population of CD8+CD122+PD-1+ Tregs in the azoxymethane-dextran sodium sulfate model of colitis-associated CRC. Moreover, silencing of tumor-derived Gal-1 in the syngeneic CT26 CRC model resulted in reduced number and attenuated immunosuppressive capacity of CD8+CD122+PD-1+ Tregs, leading to slower tumor growth. Moreover, stromal Gal-1 also influenced the fitness of CD8+ Tregs, highlighting the contribution of both tumor and stromal-derived Gal-1 to this immunoregulatory effect. Finally, bioinformatic analysis of a colorectal adenocarcinoma from The Cancer Genome Atlas dataset revealed a particular signature characterized by high CD8+ Treg score and elevated Gal-1 expression, which delineates poor prognosis in human CRC. Our findings identify CD8+CD122+PD-1+ Tregs as a target of the immunoregulatory activity of Gal-1, suggesting a potential immunotherapeutic strategy for the treatment of CRC.
Subject(s)
Adenocarcinoma/genetics , CD8-Positive T-Lymphocytes/immunology , Colitis/genetics , Colorectal Neoplasms/genetics , Galectin 1/genetics , T-Lymphocytes, Regulatory/immunology , Adenocarcinoma/immunology , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Animals , Atlases as Topic , Azoxymethane/administration & dosage , CD8-Positive T-Lymphocytes/pathology , Cell Line, Tumor , Colitis/chemically induced , Colitis/immunology , Colitis/mortality , Colorectal Neoplasms/immunology , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Computational Biology , Dextran Sulfate/administration & dosage , Disease Models, Animal , Galectin 1/deficiency , Galectin 1/immunology , Gene Expression Regulation, Neoplastic , Humans , Interleukin-2 Receptor beta Subunit/genetics , Interleukin-2 Receptor beta Subunit/immunology , Mice , Mice, Knockout , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/immunology , Signal Transduction , Survival Analysis , T-Lymphocytes, Regulatory/pathology , Tumor BurdenABSTRACT
The vast range and complexity of glycan structures and their dynamic variations in health and disease have presented formidable challenges toward understanding the biological significance of these molecules. Despite these limitations, compelling evidence highlights a major role for galectins, a family of soluble glycan-binding proteins, as endogenous decoders that translate glycan-containing information into a broad spectrum of cellular responses by modulating receptor clustering, reorganization, endocytosis, and signaling. Here, we underscore pioneer findings and recent advances in understanding the biology of galectin-glycan interactions in myeloid, lymphoid, and endothelial compartments, highlighting important pathways by which these multivalent complexes control immune and vascular programs. Implementation of novel glycoanalytical approaches, as well as the use of genetically engineered cell and organism models, have allowed glycans and galectins to be explored across a range of cellular processes.
Subject(s)
Endothelium/metabolism , Immune System/metabolism , Polysaccharides/immunology , Polysaccharides/metabolism , Signal Transduction , Galectins/metabolism , Humans , Polysaccharides/chemistryABSTRACT
Immune-related adverse events (IrAEs) affecting the gastrointestinal (GI) tract and liver are among the most frequent and most severe inflammatory toxicities from contemporary immunotherapy. Inflammation of the colon and or small intestines (entero)colitis is the single most common GI IrAE and is an important cause of delay of discontinuation of immunotherapy. The severity of these GI IrAEs can range from manageable with symptomatic treatment alone to life-threatening complications, including perforation and liver failure. The frequency and severity of GI IrAEs is dependent on the specific immunotherapy given, with cytotoxic T lymphocyte antigen (CTLA)-4 blockade more likely to induce severe GI IrAEs than blockade of either programmed cell death protein 1 (PD-1) or PD-1 ligand (PD-L1), and combination therapy showing the highest rate of GI IrAEs, particularly in the liver. To date, we have minimal prospective data on the appropriate diagnosis and management of GI IrAEs, and recommendations are based largely on retrospective data and expert opinion. Although clinical diagnoses of GI IrAEs are common, biopsy is the gold standard for diagnosis of both immunotherapy-induced enterocolitis and hepatitis and can play an important role in excluding competing, though less common, diagnoses and ensuring optimal management. GI IrAEs typically respond to high-dose corticosteroids, though a significant fraction of patients requires secondary immune suppression. For colitis, both TNF-α blockade with infliximab and integrin inhibition with vedolizumab have proved highly effective in corticosteroid-refractory cases. Detailed guidelines have been published for the management of low-grade GI IrAEs. In the setting of more severe toxicities, involvement of a GI specialist is generally recommended. The purpose of this review is to survey the available literature and provide management recommendations focused on the GI specialist.
Subject(s)
Chemical and Drug Induced Liver Injury/therapy , Gastrointestinal Diseases/chemically induced , Gastrointestinal Diseases/therapy , Immune Checkpoint Inhibitors/adverse effects , Immunotherapy/adverse effects , Neoplasms/therapy , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , Chemical and Drug Induced Liver Injury/epidemiology , Chemical and Drug Induced Liver Injury/pathology , Gastrointestinal Diseases/epidemiology , Gastrointestinal Diseases/pathology , History, 21st Century , Humans , Immune Checkpoint Inhibitors/therapeutic use , Immunologic Factors/adverse effects , Immunologic Factors/therapeutic use , International Agencies/organization & administration , International Agencies/standards , Palliative Care/organization & administration , Palliative Care/standards , Palliative Medicine/organization & administration , Palliative Medicine/standards , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Severity of Illness Index , Societies, Medical/organization & administration , Societies, Medical/standardsABSTRACT
Despite the success and ongoing promise of monoclonal antibody-targeted immune checkpoint inhibitor immunotherapy of advanced malignancies, in particular, antibodies directed against CTLA-4 and PD-1/PD-L1, the development of immune-related adverse events (irAEs) remains a constraint of this type of therapy. Although rarely fatal, the occurrence of irAEs may necessitate discontinuation of immunotherapy, as well as administration of corticosteroids or other immunosuppressive therapies that may not only compromise efficacy but also predispose for development of opportunistic infection. Clearly, retention of efficacy of immune checkpoint-targeted therapies with concurrent attenuation of immune-mediated toxicity represents a formidable challenge. In this context, the current brief review examines mechanistic relationships between these events, as well as recent insights into immunopathogenesis, and strategies which may contribute to resolving this issue. These sections are preceded by brief overviews of the discovery and functions of CTLA-4 and PD-1, as well as the chronology of the development of immunotherapeutic monoclonal antibodies which target these immune checkpoint inhibitors.
Subject(s)
Antineoplastic Agents, Immunological/adverse effects , Drug-Related Side Effects and Adverse Reactions , Immunotherapy/adverse effects , Neoplasms/therapy , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/etiology , Drug-Related Side Effects and Adverse Reactions/prevention & control , Humans , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/therapeutic use , Immunologic Factors/adverse effects , Immunologic Factors/therapeutic use , Medical Oncology/methods , Medical Oncology/trends , Neoplasms/epidemiology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunologyABSTRACT
The immune checkpoints associated with the CTLA-4 and PD-1 pathways are critical modulators of immune activation. These pathways dampen the immune response by providing brakes on activated T cells, thereby ensuring more uniform and controlled immune reactions and avoiding immune hyper-responsiveness and autoimmunity. Cancer cells often exploit these regulatory controls through a variety of immune subversion mechanisms, which facilitate immune escape and tumor survival. Immune checkpoint inhibitors (ICI) effectively block negative regulatory signals, thereby augmenting immune attack and tumor killing. This process is a double-edged sword in which release of regulatory controls is felt to be responsible for both the therapeutic efficacy of ICI therapy and the driver of immune-related adverse events (IrAEs). These adverse immune reactions are common, typically low-grade and may affect virtually every organ system. In the early clinical trials, lung IrAEs were rarely described. However, with ever-expanding clinical applications and more complex ICI-containing regimens, lung events, in particular, pneumonitis, have become increasingly recognized. ICI-related lung injury is clinically distinct from other types of lung toxicity and may lead to death in advanced stage disease. Thus, knowledge regarding the key characteristics and optimal treatment of lung-IrAEs is critical to good outcomes. This review provides an overview of lung-IrAEs, including risk factors and epidemiology, as well as clinical, radiologic, and histopathologic features of ICI-related lung injury. Management principles for ICI-related lung injury, including current consensus on steroid refractory pneumonitis and the use of other immune modulating agents in this setting are also highlighted.
Subject(s)
Immunologic Factors/adverse effects , Immunotherapy/adverse effects , Lung Diseases/chemically induced , Lung Diseases/therapy , Neoplasms/therapy , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , History, 21st Century , Humans , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/therapeutic use , Immunologic Factors/therapeutic use , International Agencies/organization & administration , International Agencies/standards , Lung Diseases/epidemiology , Palliative Care/organization & administration , Palliative Care/standards , Palliative Medicine/organization & administration , Palliative Medicine/standards , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Severity of Illness Index , Societies, Medical/organization & administration , Societies, Medical/standardsABSTRACT
Immune checkpoint inhibitors (ICIs) frequently result in cutaneous immune-related adverse events (IrAEs). Although the majority of these events are mild-to-moderate in severity, up to 5% are severe, which may lead to morbidity and dose interruption or discontinuation of ICI therapy. In addition, up to 25% of dermatologic IrAEs are corticosteroid-refractory or corticosteroid-dependent. These 2020 MASCC recommendations cover the diagnosis and management of cutaneous IrAEs with a focus on moderate-to-severe and corticosteroid-resistant events. Although the usage of immune-suppressive therapy has been advocated in this setting, there is a lack of randomized clinical trial data to provide a compelling level of evidence of its therapeutic benefit.
Subject(s)
Drug Eruptions/therapy , Immune Checkpoint Inhibitors/adverse effects , Neoplasms/therapy , Palliative Care , Drug Eruptions/etiology , Drug Eruptions/pathology , History, 21st Century , Humans , Immunotherapy/adverse effects , International Agencies/organization & administration , International Agencies/standards , Neoplasms/immunology , Palliative Care/methods , Palliative Care/standards , Palliative Medicine/organization & administration , Palliative Medicine/standards , Severity of Illness Index , Societies, Medical/organization & administration , Societies, Medical/standardsABSTRACT
Immune checkpoint inhibitors (ICIs) have emerged as the newest pillar of cancer treatment. Immune-mediated toxicities, stemming from increased activity within the T cell lineage, range from asymptomatic or mild complications to those that are fulminant and potentially fatal. Although they are of variable occurrence, cardiovascular, rheumatic, and renal immune-mediated toxicities are among the most serious of these adverse events. We present MASCC recommendations with respect to the workup and management of cardiovascular, rheumatic, and renal immune-mediated toxicities with a focus on presentations that require treatment with immunomodulating agents.
Subject(s)
Cardiovascular Diseases/therapy , Drug-Related Side Effects and Adverse Reactions/therapy , Immune Checkpoint Inhibitors/adverse effects , Immunotherapy/adverse effects , Kidney Diseases/therapy , Rheumatic Diseases/therapy , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , Cardiovascular Diseases/chemically induced , Cardiovascular Diseases/epidemiology , Drug-Related Side Effects and Adverse Reactions/etiology , History, 21st Century , Humans , Immune Checkpoint Inhibitors/therapeutic use , Immunologic Factors/adverse effects , Immunologic Factors/therapeutic use , International Agencies/organization & administration , International Agencies/standards , Kidney Diseases/chemically induced , Kidney Diseases/epidemiology , Neoplasms/epidemiology , Neoplasms/immunology , Neoplasms/therapy , Palliative Care/organization & administration , Palliative Care/standards , Palliative Medicine/organization & administration , Palliative Medicine/standards , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Rheumatic Diseases/chemically induced , Rheumatic Diseases/epidemiology , Severity of Illness Index , Societies, Medical/organization & administration , Societies, Medical/standardsABSTRACT
Immune checkpoint inhibitors (ICIs) have emerged as the newest pillar of cancer treatment, transforming outcomes in melanoma and showing benefit in a range of malignancies. Immune-mediated toxicities, stemming from increased activity within the T cell lineage, range from asymptomatic or mild complications to those that are fulminant and potentially fatal. Immune-mediated endocrinopathies include hypophysitis, thyroiditis, and insulin-dependent diabetes mellitus. These presentations, which may be vague and non-specific, can be life-threatening if not diagnosed and treated appropriately. This review considers the work-up and management of immune-mediated endocrinopathies and also considers the role of advanced practice practitioners in the management of immune-mediated toxicities. These state-of-the-art MASCC recommendations represent a comprehensive overview of the management and clinical work-up in those in whom the diagnosis should be considered.
Subject(s)
Endocrine System Diseases/therapy , Immune Checkpoint Inhibitors/adverse effects , Immunotherapy/adverse effects , Neoplasms/therapy , Physician's Role , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/therapy , Endocrine System Diseases/chemically induced , Endocrine System Diseases/epidemiology , History, 21st Century , Humans , Immune Checkpoint Inhibitors/therapeutic use , Immunologic Factors/adverse effects , Immunologic Factors/therapeutic use , International Agencies/organization & administration , International Agencies/standards , Medical Oncology/organization & administration , Medical Oncology/standards , Neoplasms/epidemiology , Neoplasms/immunology , Palliative Care/organization & administration , Palliative Care/standards , Palliative Medicine/organization & administration , Palliative Medicine/standards , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Severity of Illness Index , Societies, Medical/organization & administration , Societies, Medical/standardsABSTRACT
Galectin-1 (Gal-1), a glycan-binding protein with broad antiinflammatory activities, functions as a proresolving mediator in autoimmune and chronic inflammatory disorders. However, its role in allergic airway inflammation has not yet been elucidated. We evaluated the effects of Gal-1 on eosinophil function and its role in a mouse model of allergic asthma. Allergen exposure resulted in airway recruitment of Gal-1-expressing inflammatory cells, including eosinophils, as well as increased Gal-1 in extracellular spaces in the lungs. In vitro, extracellular Gal-1 exerted divergent effects on eosinophils that were N-glycan- and dose-dependent. At concentrations ≤0.25 µM, Gal-1 increased eosinophil adhesion to vascular cell adhesion molecule-1, caused redistribution of integrin CD49d to the periphery and cell clustering, but inhibited ERK(1/2) activation and eotaxin-1-induced migration. Exposure to concentrations ≥1 µM resulted in ERK(1/2)-dependent apoptosis and disruption of the F-actin cytoskeleton. At lower concentrations, Gal-1 did not alter expression of adhesion molecules (CD49d, CD18, CD11a, CD11b, L-selectin) or of the chemokine receptor CCR3, but decreased CD49d and CCR3 was observed in eosinophils treated with higher concentrations of this lectin. In vivo, allergen-challenged Gal-1-deficient mice exhibited increased recruitment of eosinophils and CD3(+) T lymphocytes in the airways as well as elevated peripheral blood and bone marrow eosinophils relative to corresponding WT mice. Further, these mice had an increased propensity to develop airway hyperresponsiveness and displayed significantly elevated levels of TNF-α in lung tissue. This study suggests that Gal-1 can limit eosinophil recruitment to allergic airways and suppresses airway inflammation by inhibiting cell migration and promoting eosinophil apoptosis.
Subject(s)
Asthma/etiology , Eosinophilia/etiology , Galectin 1/physiology , Animals , Apoptosis , Cell Adhesion , Chemokines/analysis , Cytokines/analysis , Eosinophils/physiology , Galectin 1/analysis , Lung/chemistry , Mice , Mice, Inbred C57BLABSTRACT
Recent understanding of the mechanisms that control immune system homeostasis and orchestrate antitumor responses has prompted the development of novel immunotherapeutic modalities. These include antibodies that target immune checkpoints such as PD-1/PD-L1 and CTLA-4, agonistic antibodies of costimulatory molecules such as CD137 and OX-40 and the adoptive transfer of genetically-modified antitumor T cells. However, a large number of patients do not respond to these therapies and develop resistance as a result of activation of compensatory circuits. Rational combination of immunotherapeutic modalities will help overcome resistance and will increase the number of patients who will benefit from these treatments. Moreover, identification of predictive biomarkers will allow selection of patients responding to these treatments. Emerging clinical trials and pre-clinical studies have shown exciting results anticipating new horizons in the design and implementation of cancer immunotherapeutic modalities.
Subject(s)
Immunotherapy/trends , Neoplasms/therapy , Antibodies, Monoclonal/immunology , CTLA-4 Antigen , Humans , Immunotherapy/methods , Neoplasms/immunology , T-Lymphocytes/immunology , Tumor Microenvironment/immunologyABSTRACT
Myeloid-derived suppressor cells (MDSCs) are key regulatory cells that control inflammation and promote tumor-immune escape. To date, no specific immunomodulatory drug has proven efficacy in targeting the expansion and/or function of these cells in different pathophysiologic settings. In this study, we identified a context-dependent effect of the nonsteroidal anti-inflammatory drug indomethacin (IND) on MDSCs, depending on whether they were derived from tumor microenvironments (TME) or from tumor-free microenvironments (TFME). Treatment of mice bearing the LP07 lung adenocarcinoma with IND inhibited the suppressive activity of splenic MDSCs, which restrained tumor growth through mechanisms involving CD8(+) T cells. The same effect was observed when MDSCs were treated with IND and conditioned media from LP07 tumor cells in vitro. However, in the absence of a tumor context, IND enhanced the intrinsic suppressive function of MDSCs and amplified their protumoral activity. In a model of autoimmune neuroinflammation, IND-treated MDSCs differentiated in TFME attenuated inflammation, whereas IND-treated MDSCs differentiated in TME aggravated clinical symptoms and delayed resolution of the disease. Mechanistically, IND reduced arginase activity as well as NO and reactive oxygen species production in MDSCs differentiated in TME but not in TFME. Moreover, expression of the C/EBP-ß transcription factor isoforms correlated with the suppressive activity of IND-treated MDSCs. Our study unveils the dual and context-dependent action of IND, a drug that serves both as an anti-inflammatory and anticancer agent, which differentially affects MDSC activity whether these cells are derived from TME or TFME. These results have broad clinical implication in cancer, chronic inflammation and autoimmunity.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cellular Microenvironment/drug effects , Cellular Microenvironment/immunology , Indomethacin/pharmacology , Myeloid Cells/drug effects , Myeloid Cells/immunology , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Animals , Autoimmunity/drug effects , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Female , Immunophenotyping , Mice , Models, Biological , Myeloid Cells/metabolism , Neoplasms/immunology , Neoplasms/pathology , Nitric Oxide/metabolism , Phenotype , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Tumor Burden/drug effects , Tumor Burden/immunologyABSTRACT
Galectins are a family of ß-galactoside-binding lectins carrying at least one consensus sequence in the carbohydrate-recognition domain. Properties of glycosylated ligands, such as N- and O-glycan branching, LacNAc (N-acetyl-lactosamine) content and the balance of α2,3- and α2,6-linked sialic acid dramatically influence galectin binding to a preferential set of counter-receptors. The presentation of specific glycans in galectin-binding partners is also critical, as proper orientation and clustering of oligosaccharide ligands on multiple carbohydrate side chains increase the binding avidity of galectins for particular glycosylated receptors. When galectins are released from the cells, they typically concentrate on the cell surface and the local matrix, raising their local concentration. Thus galectins can form their own multimers in the extracellular milieu, which in turn cross-link glycoconjugates on the cell surface generating galectin-glycan complexes that modulate intracellular signalling pathways, thus regulating cellular processes such as apoptosis, proliferation, migration and angiogenesis. Subtle changes in receptor expression, rates of protein synthesis, activities of Golgi enzymes, metabolite concentrations supporting glycan biosynthesis, density of glycans, strength of protein-protein interactions at the plasma membrane and stoichiometry may modify galectin-glycan complexes. Although galectins are key contributors to the formation of these extended glycan complexes leading to promotion of receptor segregation/clustering, and inhibition of receptor internalization by surface retention, when these complexes are disrupted, some galectins, particularly galectin-3 and -4, showed the ability to drive clathrin-independent mechanisms of endocytosis. In the present review, we summarize the data available on the assembly, hierarchical organization and regulation of conspicuous galectin-glycan complexes, and their implications in health and disease.
Subject(s)
Apoptosis/physiology , Galectin 3/metabolism , Galectin 4/metabolism , Oligosaccharides/metabolism , Receptors, Cell Surface/metabolism , Signal Transduction/physiology , Animals , Endocytosis/physiology , Galectin 3/genetics , Galectin 4/genetics , Humans , Oligosaccharides/genetics , Receptors, Cell Surface/geneticsABSTRACT
Non-melanoma skin cancer (NMSC) has risen dramatically as a result of chronic exposure to sunlight ultraviolet (UV) radiation, climatic changes and clinical conditions associated with immunosuppression. In spite of considerable progress, our understanding of the mechanisms that control NMSC development and their associated molecular and immunological landscapes is still limited. Here we demonstrated a critical role for galectin-7 (Gal-7), a ß-galactoside-binding protein preferentially expressed in skin tissue, during NMSC development. Transgenic mice (Tg46) overexpressing Gal-7 in keratinocytes showed higher number of papillomas compared to WT mice or mice lacking Gal-7 (Lgals7-/-) when subjected to a skin carcinogenesis protocol, in which tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA) and tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) were sequentially administered. RNAseq analysis of Tg46 tumor lesions revealed a unique profile compatible with cells of the myelomonocytic lineage infiltrating these tumors, an effect that was substantiated by a higher number of CD11b+Gr1+ cells in tumor-draining lymph nodes. Heightened c-Met activation and Cxcl-1 expression in Tg46 lesions suggested a contribution of this pathway to the recruitment of these cells. Remarkably, Gal-7 bound to the surface of CD11b+Ly6ChiLy6Glo monocytic myeloid cells and enhanced their immunosuppressive activity, as evidenced by increased IL-10 and TGF-ß1 secretion, and higher T-cell inhibitory activity. In vivo, carcinogen-treated Lgals7-/- animals adoptively transferred with Gal-7-conditioned monocytic myeloid cells developed higher number of papillomas, whereas depletion of these cells in Tg46-treated mice led to reduction in the number of tumors. Finally, human NMSC biopsies showed increased LGALS7 mRNA and Gal-7 protein expression and displayed transcriptional profiles associated with myeloid programs, accompanied by elevated CXCL1 expression and c-Met activation. Thus, Gal-7 emerges as a critical mediator of skin carcinogenesis and a potential therapeutic target in human NMSC.
Subject(s)
Papilloma , Skin Neoplasms , Mice , Animals , Humans , Carcinogens , Skin Neoplasms/pathology , Papilloma/pathology , Carcinogenesis/genetics , Mice, Transgenic , Galectins/genetics , Skin/metabolism , Immunity, InnateABSTRACT
Development of an aberrant vascular network is a hallmark of the multistep pathological process of tumor growth and metastasis. In response to hypoxia, several pro-angiogenic factors are synthesized to support vascularization programs required for cancer progression. Emerging data indicate the involvement of glycans and glycan-binding proteins as critical regulators of vascular circuits in health and disease. Galectins may be regulated by hypoxic conditions and control angiogenesis in different physiopathological settings. These ß-galactoside-binding proteins may promote sprouting angiogenesis by interacting with different glycosylated receptors and triggering distinct signaling pathways. Understanding the role of galectins in tumor neovascularization will contribute to the design of novel anti-angiogenic therapies aimed at complementing current anti-cancer modalities and overcoming resistance to these treatments. Here we describe selected strategies and methods used to study the role of hypoxia-regulated galectins in the regulation of blood vessel formation.
Subject(s)
Galectins , Hypoxia , Neoplasms , Neovascularization, Pathologic , Galectins/metabolism , Humans , Hypoxia/physiopathology , Neoplasms/blood supply , Neovascularization, Pathologic/physiopathology , Signal TransductionABSTRACT
Lung cancer remains the leading cause of cancer mortality in the United States, with non-small cell lung cancer (NSCLC) accounting for around 85% of cases. Of particular concern is the poor responsiveness of this malignancy to therapy, resulting in a very low 5-year survival rate (17.4%) and a prominent tendency to progress to metastatic disease. A number of very recent studies, both pre-clinical and clinical, have implicated the neutrophil in both the pathogenesis and unsatisfactory response to therapy of NSCLC. In this context, movement of neutrophils into the tumor microenvironment (TME) is a common feature of NSCLC. Indeed neutrophils are the dominant type of immune cell in the NSCLC TME, creating a highly immunosuppressive milieu that is not only conducive to tumor growth and spread, but also represents a significant obstacle to the success of anti-tumor therapy, especially novel immunotherapies. The clinically relevant adverse impact of a neutrophil predominance both systemically and in the TME of patients with NSCLC is underscored by the negative prognostic value of both a persistent neutrophilia and, in particular, a high (≥5) neutrophil:lymphocyte ratio. On a more positive note, however, recognition of the involvement of the neutrophil in both the pathophysiology of NSCLC and treatment failure has enabled identification of neutrophil-targeted strategies that have the potential to serve as adjuncts to standard anti-cancer therapies, including immunotherapy. These strategies together with a consideration of the immunosuppressive, pro-tumorigenic properties of the neutrophil represent the major thrusts of this review.
ABSTRACT
Hypoxia, angiogenesis, and immunosuppression have been proposed to be interrelated events that fuel tumor progression and impair the clinical effectiveness of anti-tumor therapies. Here we present new mechanistic data highlighting the role of hypoxia in fine-tuning CD8 T cell exhaustion in vitro, in an attempt to reconcile seemingly opposite evidence regarding the impact of hypoxia on functional features of exhausted CD8 T cells. Focusing on the recently characterized terminally-differentiated and progenitor exhausted CD8 T cells, we found that both hypoxia and its regulated mediator, vascular endothelial growth factor (VEGF)-A, promote the differentiation of PD-1+ TIM-3+ CXCR5+ terminally exhausted-like CD8 T cells at the expense of PD-1+ TIM-3- progenitor-like subsets without affecting tumor necrosis factor (TNF)-α and interferon (IFN)-γ production or granzyme B (GZMB) expression by these subpopulations. Interestingly, hypoxia accentuated the proangiogenic secretory profile in exhausted CD8 T cells. VEGF-A was the main factor differentially secreted by exhausted CD8 T cells under hypoxic conditions. In this sense, we found that VEGF-A contributes to generation of terminally exhausted CD8 T cells during in vitro differentiation. Altogether, our findings highlight the reciprocal regulation between hypoxia, angiogenesis, and immunosuppression, providing a rational basis to optimize synergistic combinations of antiangiogenic and immunotherapeutic strategies, with the overarching goal of improving the efficacy of these treatments.
Subject(s)
CD8-Positive T-Lymphocytes/physiology , Cell Differentiation/immunology , Hypoxia , Animals , CD8-Positive T-Lymphocytes/drug effects , Cell Differentiation/drug effects , Humans , Immune Tolerance , Mice, Inbred C57BL , Spleen/cytology , Vascular Endothelial Growth Factor A/immunology , Vascular Endothelial Growth Factor A/pharmacologyABSTRACT
The development of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, with agents such as nivolumab, pembrolizumab, and cemiplimab targeting programmed cell death protein-1 (PD-1) and durvalumab, avelumab, and atezolizumab targeting PD-ligand 1 (PD-L1). Ipilimumab targets cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). These inhibitors have shown remarkable efficacy in melanoma, lung cancer, urothelial cancer, and a variety of solid tumors, either as single agents or in combination with other anticancer modalities. Additional indications are continuing to evolve. Checkpoint inhibitors are associated with less toxicity when compared to chemotherapy. These agents enhance the antitumor immune response and produce side- effects known as immune-related adverse events (irAEs). Although the incidence of immune checkpoint inhibitor pneumonitis (ICI-Pneumonitis) is relatively low, this complication is likely to cause the delay or cessation of immunotherapy and, in severe cases, may be associated with treatment-related mortality. The primary mechanism of ICI-Pneumonitis remains unclear, but it is believed to be associated with the immune dysregulation caused by ICIs. The development of irAEs may be related to increased T cell activity against cross-antigens expressed in tumor and normal tissues. Treatment with ICIs is associated with an increased number of activated alveolar T cells and reduced activity of the anti-inflammatory Treg phenotype, leading to dysregulation of T cell activity. This review discusses the pathogenesis of alveolar pneumonitis and the incidence, diagnosis, and clinical management of pulmonary toxicity, as well as the pulmonary complications of ICIs, either as monotherapy or in combination with other anticancer modalities, such as thoracic radiotherapy.
ABSTRACT
The rapid spread of the SARS-CoV-2, the causative agent of the emergent pandemic disease COVID-19, requires the urgent commitment of the immunology community to understand the adaptive immune response developed by COVID-19 convalescent patients and individuals vaccinated with different strategies and schemes, with the ultimate goal of implementing and optimizing health care and prevention policies. Currently, assessment of SARS-CoV-2-specific immunity is mainly focused on the measurement of the antibody titers and analysis of their neutralizing capacity. However, a considerable proportion of individuals lack humoral responses or show a progressive decline of SARS-CoV-2-specific neutralizing antibodies. In order to study the cellular response of convalescent patients and vaccinated individuals, we have developed the "COVID-T Platform", an optimized strategy to study SARS-CoV-2-specific T cell responses. This platform allows assessment of the nature, magnitude and persistence of antigen-specific T-cell immunity in COVID-19-convalescent patients and vaccinated individuals. Moreover, it gives the opportunity to study cellular responses against emerging coronavirus variants and to identify individuals with cross-reactive immunity against seasonal coronaviruses.
La rápida propagación del coronavirus SARS-CoV-2, agente causal de la enfermedad pandémica emergente COVID-19 y sus nuevas variantes, requiere del compromiso de la comunidad inmunológica para comprender la magnitud y naturaleza de la respuesta inmunológica adaptativa desarrollada por pacientes recuperados de COVID-19 e individuos vacunados con diferentes estrategias y protocolos, a los fines de implementar nuevas políticas sanitarias. En la actualidad, la determinación de la inmunidad contra SARS-CoV-2 se basa principalmente en la detección de anticuerpos específicos y la determinación de su actividad neutralizante. Sin embargo, a pesar de la alta sensibilidad de estos ensayos, un número considerable de pacientes e individuos vacunados carecen de respuesta humoral detectable, o evidencian una disminución rápida de la misma en el tiempo. Con el objetivo de estudiar la respuesta inmune celular desencadenada frente a SARS-CoV-2, en nuestro laboratorio desarrollamos la "Plataforma COVID-T" estrategia integral optimizada dirigida a caracterizar y monitorear la respuesta de linfocitos T específicos de SARS-CoV-2 a partir de muestras de sangre de individuos vacunados y/o recuperados de COVID-19. Esta plataforma permite evaluar la naturaleza, magnitud y persistencia de la inmunidad celular T generada tanto por la infección con SARS-CoV-2, como por distintos esquemas y protocolos de vacunación en diferentes poblaciones de individuos. Asimismo, permite evaluar la respuesta inmunológica T generada frente a nuevas variantes del virus e identificar individuos sanos resistentes a SARS-CoV-2 con inmunidad pre-existente hacia coronavirus estacionales.