Authors: Antoine Louveau, Igor Smirnov, Timothy J Keyes...

One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.

Topics: Animals; Central Nervous System; Cranial Sinuses; Female; Humans; Immune Tolerance; Immunologic Surveillance; Lymphatic Vessels; Male; Meninges; Mice, Inbred C57BL; T-Lymphocytes

PubMed: 26030524
DOI: 10.1038/nature14432

Review

Authors: Gavin P Dunn, Lloyd J Old, Robert D Schreiber...

After a century of controversy, the notion that the immune system regulates cancer development is experiencing a new resurgence. An overwhelming amount of data from animal models--together with compelling data from human patients--indicate that a functional cancer immunosurveillance process indeed exists that acts as an extrinsic tumor suppressor. However, it has also become clear that the immune system can facilitate tumor progression, at least in part, by sculpting the immunogenic phenotype of tumors as they develop. The recognition that immunity plays a dual role in the complex interactions between tumors and the host prompted a refinement of the cancer immunosurveillance hypothesis into one termed "cancer immunoediting." In this review, we summarize the history of the cancer immunosurveillance controversy and discuss its resolution and evolution into the three Es of cancer immunoediting--elimination, equilibrium, and escape.

Topics: Animals; Humans; Immunologic Surveillance; Neoplasms

PubMed: 15032581
DOI: 10.1146/annurev.immunol.22.012703.104803

Review

Authors: Luca Vago, Ivana Gojo

In spite of the recent approval of new promising targeted therapies, the clinical outcome of patients with acute myeloid leukemia (AML) remains suboptimal, prompting the search for additional and synergistic therapeutic rationales. It is increasingly evident that the bone marrow immune environment of AML patients is profoundly altered, contributing to the severity of the disease but also providing several windows of opportunity to prompt or rewire a proficient antitumor immune surveillance. In this Review, we present current evidence on immune defects in AML, discuss the challenges with selective targeting of AML cells, and summarize the clinical results and immunologic insights from studies that are testing the latest immunotherapy approaches to specifically target AML cells (antibodies, cellular therapies) or more broadly reactivate antileukemia immunity (vaccines, checkpoint blockade). Given the complex interactions between AML cells and the many components of their environment, it is reasonable to surmise that the future of immunotherapy in AML lies in the rational combination of complementary immunotherapeutic strategies with chemotherapeutics or other oncogenic pathway inhibitors. Identifying reliable biomarkers of response to improve patient selection and avoid toxicities will be critical in this process.

Topics: Animals; Humans; Immunologic Surveillance; Immunotherapy; Leukemia, Myeloid, Acute

PubMed: 32235097
DOI: 10.1172/JCI129204

Review

Authors: Bingzhe Lv, Yunpeng Wang, Dongjiang Ma...

Tumor immune microenvironment (TIME) include tumor cells, immune cells, cytokines, etc. The interactions between these components, which are divided into anti-tumor and pro-tumor, determine the trend of anti-tumor immunity. Although the immune system can eliminate tumor through the cancer-immune cycle, tumors appear to eventually evade from immune surveillance by shaping an immunosuppressive microenvironment. Immunotherapy reshapes the TIME and restores the tumor killing ability of anti-tumor immune cells. Herein, we review the function of immune cells within the TIME and discuss the contribution of current mainstream immunotherapeutic approaches to remolding the TIME. Changes in the immune microenvironment in different forms under the intervention of immunotherapy can shed light on better combination treatment strategies.

Topics: Humans; Immunologic Factors; Immunologic Surveillance; Immunotherapy; Neoplasms; Tumor Microenvironment

PubMed: 35874717
DOI: 10.3389/fimmu.2022.844142

Review

Authors: Sizhe Liu, Vasiliy Galat, Yekaterina Galat...

Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. Different from events required for T cell activation, NK cell activation is governed by the interaction of NK receptors with target cells, independent of antigen processing and presentation. Due to relatively unsophisticated cues for activation, NK cell has gained significant attention in the field of cancer immunotherapy. Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. In this review, we provide our current understandings of NK cell biology, ongoing pre-clinical and clinical development of NK cell-based therapies and discuss the progress, challenges, and future perspectives.

Topics: Animals; Clinical Trials as Topic; Humans; Immunologic Surveillance; Immunotherapy, Adoptive; Killer Cells, Natural; Lymphocyte Activation; Neoplasms; Tumor Escape

PubMed: 33407739
DOI: 10.1186/s13045-020-01014-w

Review

Authors: Luke C Davies, Stephen J Jenkins, Judith E Allen...

Tissue-resident macrophages are a heterogeneous population of immune cells that fulfill tissue-specific and niche-specific functions. These range from dedicated homeostatic functions, such as clearance of cellular debris and iron processing, to central roles in tissue immune surveillance, response to infection and the resolution of inflammation. Recent studies highlight marked heterogeneity in the origins of tissue macrophages that arise from hematopoietic versus self-renewing embryo-derived populations. We discuss the tissue niche-specific factors that dictate cell phenotype, the definition of which will allow new strategies to promote the restoration of tissue homeostasis. Understanding the mechanisms that dictate tissue macrophage heterogeneity should explain why simplified models of macrophage activation do not explain the extent of heterogeneity seen in vivo.

Topics: Animals; Humans; Immunity; Immunologic Surveillance; Inflammation; Macrophage Activation; Macrophages; Organ Specificity; Wound Healing

PubMed: 24048120
DOI: 10.1038/ni.2705

Review

Authors: Gavin P Dunn, Lloyd J Old, Robert D Schreiber...

The last fifteen years have seen a reemergence of interest in cancer immunosurveillance and a broadening of this concept into one termed cancer immunoediting. The latter, supported by strong experimental data derived from murine tumor models and provocative correlative data obtained by studying human cancer, holds that the immune system not only protects the host against development of primary nonviral cancers but also sculpts tumor immunogenicity. Cancer immunoediting is a process consisting of three phases: elimination (i.e., cancer immunosurveillance), equilibrium, and escape. Herein, we summarize the data supporting the existence of each of the three cancer immunoediting phases. The full understanding of the immunobiology of cancer immunosurveillance and immunoediting will hopefully stimulate development of more effective immunotherapeutic approaches to control and/or eliminate human cancers.

Topics: Animals; Humans; Immunity, Innate; Immunologic Surveillance; Interferon-gamma; Neoplasms; Tumor Escape

PubMed: 15308095
DOI: 10.1016/j.immuni.2004.07.017

Review

Authors: Qinghua Wu, Li You, Eugenie Nepovimova...

Hypoxia, a common feature of the tumor microenvironment in various types of cancers, weakens cytotoxic T cell function and causes recruitment of regulatory T cells, thereby reducing tumoral immunogenicity. Studies have demonstrated that hypoxia and hypoxia-inducible factors (HIFs) 1 and 2 alpha (HIF1A and HIF2A) are involved in tumor immune escape. Under hypoxia, activation of HIF1A induces a series of signaling events, including through programmed death receptor-1/programmed death ligand-1. Moreover, hypoxia triggers shedding of complex class I chain-associated molecules through nitric oxide signaling impairment to disrupt immune surveillance by natural killer cells. The HIF-1-galactose-3-O-sulfotransferase 1-sulfatide axis enhances tumor immune escape via increased tumor cell-platelet binding. HIF2A upregulates stem cell factor expression to recruit tumor-infiltrating mast cells and increase levels of cytokines interleukin-10 and transforming growth factor-β, resulting in an immunosuppressive tumor microenvironment. Additionally, HIF1A upregulates expression of tumor-associated long noncoding RNAs and suppresses immune cell function, enabling tumor immune escape. Overall, elucidating the underlying mechanisms by which HIFs promote evasion of tumor immune surveillance will allow for targeting HIF in tumor treatment. This review discusses the current knowledge of how hypoxia and HIFs facilitate tumor immune escape, with evidence to date implicating HIF1A as a molecular target in such immune escape. This review provides further insight into the mechanism of tumor immune escape, and strategies for tumor immunotherapy are suggested.

Topics: Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Immunologic Surveillance; Neoplasms; Tumor Escape; Tumor Microenvironment

PubMed: 35659268
DOI: 10.1186/s13045-022-01292-6

Authors: Almut Brand, Katrin Singer, Gudrun E Koehl...

Elevated lactate dehydrogenase A (LDHA) expression is associated with poor outcome in tumor patients. Here we show that LDHA-associated lactic acid accumulation in melanomas inhibits tumor surveillance by T and NK cells. In immunocompetent C57BL/6 mice, tumors with reduced lactic acid production (Ldha) developed significantly slower than control tumors and showed increased infiltration with IFN-γ-producing T and NK cells. However, in Rag2γc mice, lacking lymphocytes and NK cells, and in Ifng mice, Ldha and control cells formed tumors at similar rates. Pathophysiological concentrations of lactic acid prevented upregulation of nuclear factor of activated T cells (NFAT) in T and NK cells, resulting in diminished IFN-γ production. Database analyses revealed negative correlations between LDHA expression and T cell activation markers in human melanoma patients. Our results demonstrate that lactic acid is a potent inhibitor of function and survival of T and NK cells leading to tumor immune escape.

Topics: Animals; Apoptosis; CD8-Positive T-Lymphocytes; Cell Count; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cytokines; Glycolysis; Humans; Immunologic Surveillance; Interferon-gamma; Isoenzymes; Killer Cells, Natural; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5; Lactic Acid; Male; Melanoma; Mice, Inbred C57BL; NFATC Transcription Factors; Phenotype; Sodium Lactate; T-Lymphocytes; Up-Regulation

PubMed: 27641098
DOI: 10.1016/j.cmet.2016.08.011

Review

Authors: Daniel Ricklin, George Hajishengallis, Kun Yang...

Nearly a century after the significance of the human complement system was recognized, we have come to realize that its functions extend far beyond the elimination of microbes. Complement acts as a rapid and efficient immune surveillance system that has distinct effects on healthy and altered host cells and foreign intruders. By eliminating cellular debris and infectious microbes, orchestrating immune responses and sending 'danger' signals, complement contributes substantially to homeostasis, but it can also take action against healthy cells if not properly controlled. This review describes our updated view of the function, structure and dynamics of the complement network, highlights its interconnection with immunity at large and with other endogenous pathways, and illustrates its multiple roles in homeostasis and disease.

Topics: Apoptosis; Complement System Proteins; Disease; Gene Expression Regulation; Homeostasis; Humans; Immunologic Surveillance; Signal Transduction

PubMed: 20720586
DOI: 10.1038/ni.1923