Platelet-Mediated Protection of Cancer Cells From Immune Surveillance - Possible Implications for Cancer Immunotherapy.

The growing insights in the complex interactions between metastatic cancer-cells and platelets have revealed that platelet tumor cell interactions in the blood stream are an important factor supporting tumor metastasis. An increased coagulability of platelets facilitates the vascular evasion and establishment of solid tumor metastasis. Furthermore, platelets can support an immunosuppressive tumor microenvironment or shield tumor cells directly from engagement of cytotoxic lymphocytes as e.g., natural killer (NK) cells. Platelets are both in the tumor microenvironment and systemically the quantitatively most important source of TGF-ß, which is a key cytokine for immunosuppression in the tumor microenvironment. If similar platelet-tumor interactions are of physiological relevance in hematological malignancies remains less well-studied. This might be important, as T- and NK cell mediated graft vs. leukemia effects (GvL) are well-documented and malignant hematological cells have a high exposure to platelets compared to solid tumors. As NK cell-based immunotherapies gain increasing attention as a therapeutic option for patients suffering from hematological and other malignancies, we review the known interactions between platelets and NK cells in the solid tumor setting and discuss how these could also apply to hematological cancers. We furthermore explore the possible implications for NK cell therapy in patients with solid tumors and patients who depend on frequent platelet transfusions. As platelets have a protective and supportive effect on cancer cells, the impact of platelet transfusion on immunotherapy and the combination of immunotherapy with platelet inhibitors needs to be evaluated.

Effects of caloric restriction on immunosurveillance, microbiota and cancer cell phenotype: Possible implications for cancer treatment.

Fasting, caloric restriction and foods or compounds mimicking the biological effects of caloric restriction, known as caloric restriction mimetics, have been associated with a lower risk of age-related diseases, including cardiovascular diseases, cancer and cognitive decline, and a longer lifespan. Reduced calorie intake has been shown to stimulate cancer immunosurveillance, reducing the migration of immunosuppressive regulatory T cells towards the tumor bulk. Autophagy stimulation via reduction of lysine acetylation, increased sensitivity to chemo- and immunotherapy, along with a reduction of insulin-like growth factor 1 and reactive oxygen species have been described as some of the major effects triggered by caloric restriction. Fasting and caloric restriction have also been shown to beneficially influence gut microbiota composition, modify host metabolism, reduce total cholesterol and triglyceride levels, lower diastolic blood pressure and elevate morning cortisol level, with beneficial modulatory effects on cardiopulmonary fitness, body fat and weight, fatigue and weakness, and general quality of life. Moreover, caloric restriction may reduce the carcinogenic and metastatic potential of cancer stem cells, which are generally considered responsible of tumor formation and relapse. Here, we reviewed in vitro and in vivo studies describing the effects of fasting, caloric restriction and some caloric restriction mimetics on immunosurveillance, gut microbiota, metabolism, and cancer stem cell growth, highlighting the molecular and cellular mechanisms underlying these effects. Additionally, studies on caloric restriction interventions in cancer patients or cancer risk subjects are discussed. Considering the promising effects associated with caloric restriction and caloric restriction mimetics, we think that controlled-randomized large clinical trials are warranted to evaluate the inclusion of these non-pharmacological approaches in clinical practice.

Arming cytotoxic lymphocytes for cancer immunotherapy by means of the NKG2D/NKG2D-ligand system.

INTRODUCTION: The activating NKG2D receptor plays a central role in the immune recognition and elimination of abnormal self-cells by cytotoxic lymphocytes. NKG2D binding to cell stress-inducible ligands (NKG2DL) up-regulated on cancer cells facilitates their immunorecognition. Yet tumor cells utilize various escape mechanisms to avert NKG2D-based immunosurveillance. Hence, therapeutic strategies targeting the potent NKG2D/NKG2DL axis and such immune escape mechanisms become increasingly attractive in cancer therapy. AREAS COVERED: This perspective provides a brief introduction into the NKG2D/NKG2DL axis and its relevance for cancer immune surveillance. Subsequently, the most advanced therapeutic approaches targeting the NKG2D system are presented focusing on NKG2D-CAR engineered immune cells and antibody-mediated strategies to inhibit NKG2DL shedding by tumors. EXPERT OPINION: Thus far, NKG2D-CAR engineered lymphocytes represent the most advanced therapeutic approach utilizing the NKG2D system. Similarly to other tumor-targeting CAR approaches, NKG2D-CAR cells demonstrate powerful on-target activity, but may also cause off-tumor toxicities or lose efficacy, if NKG2DL expression by tumors is reduced. However, NKG2D-CAR cells also act on the tumor microenvironment curtailing its immunosuppressive properties, thus providing an independent therapeutic benefit. The potency of tumoricidal NKG2D-expressing lymphocytes can be further boosted by enhancing NKG2DL expression through small molecules and therapeutic antibodies inhibiting tumor-associated shedding of NKG2DL.

[Natural killer cells: promising targets in cancer therapy]. / Les cellules natural killer : des cibles prometteuses dans la thérapie contre le cancer.

TITLE: Les cellules natural killer : des cibles prometteuses dans la thérapie contre le cancer. ABSTRACT: L'immuno-oncologie est une approche d'immunothérapie novatrice qui change le traitement des cancers en stimulant la capacité du système immunitaire à reconnaître et éliminer les cellules tumorales. Cette approche a pour but de mettre en place une immuno-surveillance anti-tumorale durable chez des patients pour lesquels les thérapies conventionnelles ont échoué.

Structure of the Human cGAS-DNA Complex Reveals Enhanced Control of Immune Surveillance.

Cyclic GMP-AMP synthase (cGAS) recognition of cytosolic DNA is critical for immune responses to pathogen replication, cellular stress, and cancer. Existing structures of the mouse cGAS-DNA complex provide a model for enzyme activation but do not explain why human cGAS exhibits severely reduced levels of cyclic GMP-AMP (cGAMP) synthesis compared to other mammals. Here, we discover that enhanced DNA-length specificity restrains human cGAS activation. Using reconstitution of cGAMP signaling in bacteria, we mapped the determinant of human cGAS regulation to two amino acid substitutions in the DNA-binding surface. Human-specific substitutions are necessary and sufficient to direct preferential detection of long DNA. Crystal structures reveal why removal of human substitutions relaxes DNA-length specificity and explain how human-specific DNA interactions favor cGAS oligomerization. These results define how DNA-sensing in humans adapted for enhanced specificity and provide a model of the active human cGAS-DNA complex to enable structure-guided design of cGAS therapeutics.

[The biological rationale for immunotherapy in cancer]. / Rationnel biologique de l'immunothérapie des cancers.

INTRODUCTION: Immunotherapy aims to promote the immune system's activity against malignant cells by stimulating the response to several tumor antigens. STATE OF THE ART: Immunosurveillance may adjust the immunogenicity of tumors. To be effective, immunity must induce the specific activation of CD4+ and CD8+ T lymphocytes, as well as activation of innate immunity. Activator and inhibitory costimulatory molecules regulate T lymphocyte activation at immunity checkpoints such as PD-1/PD-L1 and CTLA-4. Adaptive immune resistance confers tumour resistance to immunosurveillance through these immune checkpoints. PERSPECTIVES: Approaches involving the combination of several immunotherapies with each other or with chemotherapy and radiotherapy and antibodies against other molecules of costimulation are under development. The development of biomarkers, which can select a targeted population and predict therapeutic response, represents a major challenge. Tumour high-throughput sequencing could refine "immunoscore". Intratumoral T cell receptor seems to represent a promising biomarker. CONCLUSIONS: Numerous challenges still remain in developing research approaches for the development of immunotherapies.

[The interplay of immunotherapy and chemotherapy, a novel approach]. / L'immunothérapie au service de la chimiothérapie, de nouvelles avancées.

In the last decade, a growing body of evidence has highlighted the major role of cancer immunosurveillance. The immune system can recognize tumor cells and keep them under check for long period of time, but is impeded by escape mechanisms induced by the tumor itself. Interestingly, the efficacy of chemotherapy has been shown to depend on the immune response, which in turn is potentiated by chemical agents, creating a positive feedback loop leading to long term tumor resistance. In this review, we summarize some mechanisms underlying the synergy between chemo- and immuno-therapy.

An Apparent Deficiency of Lymphatic Capillaries in the Islets of Langerhans in the Human Pancreas.

The lymphatic system is crucial for efficient immune surveillance and for the maintenance of a physiological pressure in the interstitial space. Even so, almost no information is available concerning the lymph drainage of the islets of Langerhans in the human pancreas. Immunohistochemical staining allowed us to distinguish lymphatic capillaries from blood capillaries. Almost no lymphatic capillaries were found within the islets in pancreatic biopsy specimens from subjects without diabetes or from subjects with type 1 or type 2 diabetes. Lymphatic capillaries were, however, found at the islet-exocrine interface, frequently located along blood capillaries and other fibrotic structures within or close to the islet capsule. Lymphatic capillaries were regularly found in the exocrine pancreas, with small lymphatic vessels located close to and around acini. Larger collecting lymphatic vessels were located in fibrotic septa between the exocrine lobules and adjacent to the ductal system of the pancreas. In summary, we report a pronounced deficiency of lymphatic capillaries in human islets, a finding with implications for immune surveillance and the regulation of interstitial fluid transport in the endocrine pancreas as well as for the pathophysiology of both type 1 and type 2 diabetes.

STAT3 Establishes an Immunosuppressive Microenvironment during the Early Stages of Breast Carcinogenesis to Promote Tumor Growth and Metastasis.

Immunosurveillance constitutes the first step of cancer immunoediting in which developing malignant lesions are eliminated by antitumorigenic immune cells. However, the mechanisms by which neoplastic cells induce an immunosuppressive state to evade the immune response are still unclear. The transcription factor STAT3 has been implicated in breast carcinogenesis and tumor immunosuppression in advanced disease, but its involvement in early disease development has not been established. Here, we genetically ablated Stat3 in the tumor epithelia of the inducible PyVmT mammary tumor model and found that Stat3-deficient mice recapitulated the three phases of immunoediting: elimination, equilibrium, and escape. Pathologic analyses revealed that Stat3-deficient mice initially formed hyperplastic and early adenoma-like lesions that later completely regressed, thereby preventing the emergence of mammary tumors in the majority of animals. Furthermore, tumor regression was correlated with massive immune infiltration into the Stat3-deficient lesions, leading to their elimination. In a minority of animals, focal, nonmetastatic Stat3-deficient mammary tumors escaped immune surveillance after a long latency or equilibrium period. Taken together, our findings suggest that tumor epithelial expression of Stat3 plays a critical role in promoting an immunosuppressive tumor microenvironment during breast tumor initiation and progression, and prompt further investigation of Stat3-inhibitory strategies that may reactivate the immunosurveillance program.

Recurrent turnover of senescent cells during regeneration of a complex structure.

Cellular senescence has been recently linked to the promotion of age-related pathologies, including a decline in regenerative capacity. While such capacity deteriorates with age in mammals, it remains intact in species such as salamanders, which have an extensive repertoire of regeneration and can undergo multiple episodes through their lifespan. Here we show that, surprisingly, there is a significant induction of cellular senescence during salamander limb regeneration, but that rapid and effective mechanisms of senescent cell clearance operate in normal and regenerating tissues. Furthermore, the number of senescent cells does not increase upon repetitive amputation or ageing, in contrast to mammals. Finally, we identify the macrophage as a critical player in this efficient senescent cell clearance mechanism. We propose that effective immunosurveillance of senescent cells in salamanders supports their ability to undergo regeneration throughout their lifespan.

Compartmentalizing intestinal epithelial cell toll-like receptors for immune surveillance.

Toll-like receptors (TLRs) are membrane-bound microbial sensors that mediate important host-to-microbe responses. Cell biology aspects of TLR function have been intensively studied in professional immune cells, in particular the macrophages and dendritic cells, but not well explored in other specialized epithelial cell types. The adult intestinal epithelial cells are in close contact with trillions of enteric microbes and engage in lifelong immune surveillance. Mature intestinal epithelial cells, in contrast to immune cells, are highly polarized. Recent studies suggest that distinct mechanisms may govern TLR traffic and compartmentalization in these specialized epithelial cells to establish and maintain precise signaling of individual TLRs. We, using immune cells as references, discuss here the shared and/or unique molecular machineries used by intestinal epithelial cells to control TLR transport, localization, processing, activation, and signaling. A better understanding of these mechanisms will certainly generate important insights into both the mechanism and potential intervention of leading digestive disorders, in particular inflammatory bowel diseases.

Selective inhibition of KCa3.1 channels mediates adenosine regulation of the motility of human T cells.

Adenosine, a purine nucleoside, is present at high concentrations in tumors, where it contributes to the failure of immune cells to eliminate cancer cells. The mechanisms responsible for the immunosuppressive properties of adenosine are not fully understood. We tested the hypothesis that adenosine's immunosuppressive functions in human T lymphocytes are in part mediated via modulation of ion channels. The activity of T lymphocytes relies on ion channels. KCa3.1 and Kv1.3 channels control cytokine release and, together with TRPM7, regulate T cell motility. Adenosine selectively inhibited KCa3.1, but not Kv1.3 and TRPM7, in activated human T cells. This effect of adenosine was mainly mediated by A2A receptors, as KCa3.1 inhibition was reversed by SCH58261 (selective A2A receptor antagonist), but not by MRS1754 (A2B receptor antagonist), and it was mimicked by the A2A receptor agonist CGS21680. Furthermore, it was mediated by the cAMP/protein kinase A isoform (PKAI) signaling pathway, as adenylyl-cyclase and PKAI inhibition prevented adenosine effect on KCa3.1. The functional implication of the effect of adenosine on KCa3.1 was determined by measuring T cell motility on ICAM-1 surfaces. Adenosine and CGS21680 inhibited T cell migration. Comparable effects were obtained by KCa3.1 blockade with TRAM-34. Furthermore, the effect of adenosine on cell migration was abolished by pre-exposure to TRAM-34. Additionally, adenosine suppresses IL-2 secretion via KCa3.1 inhibition. Our data indicate that adenosine inhibits KCa3.1 in human T cells via A2A receptor and PKAI, thereby resulting in decreased T cell motility and cytokine release. This mechanism is likely to contribute to decreased immune surveillance in solid tumors.

Immunosurveillance as a regulator of tissue homeostasis.

The immune system is intimately involved in the pathophysiology of several human disorders. Thus, excessive or chronic inflammation initiated by numerous insults exacerbates tissue damage and - at least in some settings - promotes oncogenesis. Nevertheless, immunosurveillance, the process whereby the immune system eliminates damaged, senescent and (pre-)malignant cells, appears to exert major homeostatic functions. Accumulating evidence indicates that defects in the molecular and cellular circuitries that underpin immune responses accelerate the course of chronic diseases, including hepatic cirrhosis and cancer. Along similar lines, the re-establishment of tissue homeostasis upon acute pathological insults such as ischemia appears to be delayed when normal immunological functions are naturally or experimentally compromised. Here, we propose that immunosurveillance is a key regulator of tissue homeostasis.

Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates.

Complex barriers separate immune-privileged tissues from the circulation. Here, we propose that cell entry to immune-privileged sites through barriers composed of tight junction-interconnected endothelium is associated with destructive inflammation, whereas border structures comprised of fenestrated vasculature enveloped by tightly regulated epithelium serve as active and selective immune-skewing gates in the steady state. Based on emerging knowledge of the central nervous system and information from other immune-privileged sites, we propose that these sites are endowed either with absolute endothelial-based barriers and epithelial gates that enable selective and educative transfer of trafficking leukocytes or with selective epithelial gates only.

TNF-induced target cell killing by CTL activated through cross-presentation.

Viruses can escape cytotoxic T cell (CTL) immunity by avoiding presentation of viral components via endogenous MHC class I antigen presentation in infected cells. Cross-priming of viral antigens circumvents such immune escape by allowing noninfected dendritic cells to activate virus-specific CTLs, but they remain ineffective against infected cells in which immune escape is functional. Here, we show that cross-presentation of antigen released from adenovirus-infected hepatocytes by liver sinusoidal endothelial cells stimulated cross-primed effector CTLs to release tumor necrosis factor (TNF), which killed virus-infected hepatocytes through caspase activation. TNF receptor signaling specifically eliminated infected hepatocytes that showed impaired anti-apoptotic defense. Thus, CTL immune surveillance against infection relies on two similarly important but distinct effector functions that are both MHC restricted, requiring either direct antigen recognition on target cells and canonical CTL effector function or cross-presentation and a noncanonical effector function mediated by TNF.

Neoplastic "Black Ops": cancer's subversive tactics in overcoming host defenses.

Metastatic cancer is usually an incurable disease. Cancers have a broad repertoire of subversive tactics to defeat the immune system. They mimic self, they down-regulate MHC molecules so that T cells are blind to their presence, they interfere with antigen presentation, and they produce factors that can kill T cells or paralyze their response to antigens. Furthermore, the same powerful machinery designed to prevent harmful autoimmune responses is also acting to protect cancers. In particular, cancer is protected with the help of so-called regulatory immune cells. These unique subsets of cells, represented by almost every immune cell type, function to control responses of effector immune cells. In this review, we will discuss the evidence that cancer actively promotes cross-talk of regulatory immune cells to evade immunosurveillance. We will also discuss the role of a newly described cell type, regulatory B cells, by emphasizing their importance in suppression of antitumor immune responses. Thus, cancer not only directly suppresses immune function, but also recruits components of the immune system to become traitors and protect the tumor from immune attack.

Inflammation and immune surveillance in cancer.

Chronic inflammation is a risk factor for tumor development. However, understanding the effect of the immune system on tumor development has only been significantly advanced over the past two decades. We now appreciate that the immune system, in addition to tumor-suppressive function by eliminating nascent transformed tumor cells, can also exert selection pressure on tumor cells and facilitate tumor growth by providing a favorable tumor microenvironment. Yet, the distinctions between tumor-promoting inflammation and tumor-suppressive immunity are still not clear due to the dual role of some cytokines and other molecules in the immune system. The danger signal hypothesis has shaped our view of the role of immunity in cancer development, but still little is known about the exact role of danger signal receptors in cancer progression. In this review, we introduce the processes of cancer immunoediting and inflammation-induced cancer and discuss what is currently known about the role of danger signal receptors in cancer development and progression.