Regulatory T cell: a protection for tumour cells

Characterized by immunosuppression regulatory T cells (Tregs) play a key role in maintaining immune tolerance. A growing number of tumours have been found with Tregs accumulating in microenvironment and patients with high density of Tregs in tumour stroma get a worse prognosis, which suggests that Tregs may inhibit anti-tumour immunity in stroma, resulting in a poor prognosis. In this paper, we demonstrate the accumulation of Tregs in tumour stroma and the possible suppressive mechanisms. We also state the immunotherapy that has being used in animal and clinical trials.     

Roles of exosomal circRNAs in tumour immunity and cancer progression

Tumour immunity plays an important role in the development of cancer. Tumour immunotherapy is an important component of antitumour therapy. Exosomes, a type of extracellular vesicle, act as mediators of intercellular communication and molecular transfer and play an essential role in tumour immunity. Circular RNAs (circRNAs) are a new type of noncoding RNA that are enriched within exosomes. In this review, we describe the effects of exosomal circRNAs on various immune cells and the mechanisms of these effects, including macrophages, neutrophils, T cells, and Natural killer (NK) cells. Next, we elaborate on the latest progress of exosome extraction. In addition, the function of exosomal circRNAs as a potential prognostic and drug sensitivity marker is described. We present the great promise of exosomal circRNAs in regulating tumour immunity, predicting patient outcomes, and evaluating drug efficacy.Subject terms: Tumour immunology, Cancer microenvironment, Tumour biomarkers, Oncogenes     

Experimental mouse tumour models: what can be learnt about human cancer immunology?

The recent demonstration that cancer immunotherapy extends patient survival has reinvigorated interest in elucidating the role of immunity in tumour pathogenesis. Experimental mouse tumour models have provided key mechanistic insights into host antitumour immune responses, and these have guided the development of novel treatment strategies. To accelerate the translation of these findings into clinical benefits, investigators need to gain a better understanding of the strengths and limitations of mouse model systems as tools for deciphering human antitumour immune responses.     

Chemokines: agents for the immunotherapy of cancer?

Chemokines, a superfamily of small cytokine-like molecules, regulate leukocyte transport in the body. In recent years, we have witnessed the transition of immunotherapeutic strategies from the laboratory to the bedside. Here, we review the role of chemokines in tumour biology and the development of the host's anti-tumour defence. We summarize the current knowledge of chemokine-receptor expression by relevant cellular components of the immune system and the role of their ligands in the organization of the antitumour immune response. Finally, we discuss recent findings which indicate that chemokines have therapeutic potential as adjuvants or treatments in antitumour immunotherapy, as well as remaining questions and perspectives for translating experimental evidence into clinical practice.     

Regulatory T cells in skeletal muscle repair and regeneration: recent insights

Skeletal muscle repair and regeneration after injury is a multi-stage process, involving a dynamic inflammatory microenvironment consisting of a complex network formed by the interaction of immune cells and their secreted cytokines. The homeostasis of the inflammatory microenvironment determines whether skeletal muscle repair tissues will ultimately form scar tissue or regenerative tissue. Regulatory T cells (Tregs) regulate homeostasis within the immune system and self-immune tolerance, and play a crucial role in skeletal muscle repair and regeneration. Dysregulated Tregs function leads to abnormal repair. In this review, we discuss the role and mechanisms of Tregs in skeletal muscle repair and regeneration after injury and provide new strategies for Treg immunotherapy in skeletal muscle diseases.Subject terms: Trauma, Immunotherapy     

IL-2 immunotoxin therapy modulates tumor-associated regulatory T cells and leads to lasting immune-mediated rejection of breast cancers in neu-transgenic mice

Studies in cancer patients have suggested that breast tumors recruit regulatory T cells (Tregs) into the tumor microenvironment. The extent to which local Tregs suppress antitumor immunity in breast cancer is unknown. We questioned whether inhibiting systemic Tregs with an IL-2 immunotoxin in a model of neu-mediated breast cancer, the neu-transgenic mouse, could impact disease progression and survival. As in human breast cancer, cancers that develop in these mice attract Tregs into the tumor microenvironment to levels of approximately 10-25% of the total CD4+ T cells. To examine the role of Tregs in blocking immune-mediated rejection of tumor, we depleted CD4+CD25+ T cells with an IL-2 immunotoxin. The treatment depleted Tregs without concomitant lymphopenia and markedly inhibited tumor growth. Depletion of Tregs resulted in a persistent antitumor response that was maintained over a month after the last treatment. The clinical response was immune-mediated because adoptive transfer of Tregs led to a complete abrogation of the therapeutic effects of immunotoxin treatment. Further, Treg down-modulation was accompanied by increased Ag-specific immunity against the neu protein, a self Ag. These results suggest that Tregs play a major role in preventing an effective endogenous immune response against breast cancer and that depletion of Tregs, without any additional immunotherapy, may mediate a significant antitumor response.     

Tumour escape mechanisms and their therapeutic implications in combination tumour therapy

Most tumours arise from a single normal cell through a sequential evolutionary process of mutation and selection. Tumours are initiated by escaping non‐immune surveillance, which includes defective DNA repair, epigenetic gene alternation, resistance to apoptosis and loss of intercellular contact inhibition. Tumour cells harbour mutations in a number of critical genes that provide selective advantages at various stages during the evolution of the tumour. The tumour cells that circumvent the tumour suppressor mechanisms of the non‐immune surveillance process are edited by the immune system, resulting in the selection of a resistant tumour variant. The selection of the tumour cell is further shaped by its interactions with cells and other factors in its microenvironment. Tumour evolution is thought to adhere to Darwinian principles by escaping both non‐immune (intrinsic) and immune (extrinsic) responses against self‐altered tumour cells. At end‐stage, tumours have escaped both non‐immune and immune surveillance with increased threshold of apoptosis. Combination therapy has been proposed, by exploring the non‐immune and immune suppressive nature of the tumour, and has been found to have a therapeutic efficiency on tumour regression as compared with monotherapies. The combination of immunotherapy and other different modalities, especially vaccines, with conventional anticancer therapies with optimized dosage and scheduling can offer synergistic antitumour effects. Here, we focus on the mechanism of tumour evolution and its implication in combination therapy.     

Tumour-draining lymph nodes in head and neck cancer are characterized by accumulation of CTLA-4 and PD-1 expressing Treg cells

IntroductionHigh Tregs infiltration within the tumour microenvironment (TME) of various cancers shows a positive correlation with poor prognosis. Despite the fact that tumour draining lymph nodes (TDLNs) are recognized as key organs playing a crucial role in response to immunotherapy and modulating anti-cancer immunity, the distribution of Tregs and their role in TDLNs remain uncertain thus far. The purpose of this project is to investigate the density of Tregs in TDLNs and non-TDLNs and their expression of immune checkpoint molecules – PD-1 and CTLA-4.MethodsSamples including TDLNs, non-TDLNs and metastatic lymph nodes (LNs) from 23 patients with oral squamous cell carcinoma (OSCC) were analyzed by multicolour flow cytometry with a focus on Tregs population and expression of CTLA-4 and PD-1.ResultsTDLNs and metastatic LNs were characterized by a significantly higher infiltration of Tregs defined as CD4+FoxP3+CD25^highCD127^low cells and significantly higher expression of CTLA-4 and PD-1 on Tregs compared with non-TDLNs. Tregs in TDLNs and metastatic LNs co-expressed CTLA-4 and PD-1 abundantly. High expression of these immune check-point molecules correlated with positive N-stage but not with T-stage.ConclusionTDLNs and metastatic LNs are characterized by a high accumulation of Tregs expressing high levels of CTLA-4 and PD-1. High infiltration of Tregs can be a potential driver of an immunosuppressive milieu in TDLNs that can, in turn, favour cancer progression. High accumulation of Tregs expressing CTLA-4 and PD-1 in TDLNs is associated with lymph node involvement, but not with the size of the primary tumour.     

Immunization with a GM3 ganglioside nanoparticulated vaccine confers an effector CD8<Superscript>+</Superscript> T cells-mediated protection against melanoma B16 challenge

Preventive immunotherapy is an attractive strategy for patients at a high risk of having cancer. The success of prophylactic cancer vaccines would depend on the selection of target antigens that are essential for tumour growth and progression. The overexpression of GM3 ganglioside in murine and human melanomas and its important role in tumour progression makes this self antigen a potential target for preventive immunotherapy of this neoplasm. We have previously shown that preventive administration of a GM3-based vaccine to C57BL/6 mice elicited the rejection of the GM3 positive-B16 melanoma cells in most of the animals. Despite the crucial role of cellular immune response in tumour protection, the involvement of T cells in anti-tumour immunity of ganglioside vaccines is not described. Here, we examined the mechanisms by which this immunogen confers tumour protection. We have found that induction of anti-GM3 IgG antibodies correlated with tumour protection. Surprisingly, CD8⁺ T cells, but not NK1.1⁺ cells, are required in the effector phase of the antitumour immune response. The depletion of CD4⁺ T cells during immunization phase did not affect the anti-tumour activity. In addition, T cells from surviving-immunized animals secreted IFNγ when were co-cultured with IFNα-treated B16 melanoma cells or DCs pulsed with melanoma extract. Paradoxically, in spite of the glycolipidic nature of this antigen, these findings demonstrate the direct involvement of the cellular immune response in the anti-tumour protection induced by a ganglioside-based vaccine. Grant support: Center of Molecular Immunology, Elea Laboratories and Recombio.     

Homeostasis and Function of Regulatory T Cells in HIV/SIV Infection

Regulatory T cells (Tregs) play a pivotal role in the maintenance of tolerance as well as in the control of immune activation, particularly during chronic infections. In the setting of HIV infection, the majority of studies have reported an increase in Treg frequency but a decrease in absolute number in all immune compartments of HIV-infected individuals. Several nonexclusive mechanisms have been postulated to explain this preferential Treg accumulation, including peripheral survival, increased proliferation, increased peripheral conversion, and tissue redistribution. The role played by Tregs during HIV infection is still poorly understood, as two opposing hypotheses have been proposed. A detrimental role of Tregs during HIV infection was suggested based on the evidence that Tregs suppress virus-specific immune responses. Conversely, Tregs could be beneficial by limiting immune activation, thus controlling the availability of HIV targets as well as preventing immune-based pathologies. Despite the technical difficulties, getting a better understanding of the mechanisms regulating Treg dynamics remains important, as it will help determine whether we can successfully manipulate Treg function or number to the advantage of the infected host. The aim of this review is thus to discuss the recent findings on Treg homeostasis and function in the setting of HIV infection.     

Immunological responses can have both pro- and antitumour effects: implications for immunotherapy

Immune responses influence the development and progression of a malignancy. The tumour can also manipulate the immune system to its own ends, often resulting in an ineffective or transient antitumour response. An appreciation of the complexity of these host-tumour interactions is therefore important for the development of more-effective cancer therapies. This article highlights some prominent mechanisms whereby tumours escape recognition and destruction by the host immune system, thus facilitating disease progression. One important consequence of tumour escape is that an antitumour immune response may unintentionally lead to the outgrowth of less immunogenic or more apoptosis-resistant tumour escape variants, which possess enhanced tumourigenic potential. Insights into the molecular mechanisms of cancer evasion and the complexity of the ever-changing interactions between host and tumour will enable a more rational design of antitumour therapies and may help not only explain disease recurrence, but also identify potential targets for therapeutic interventions. This article also offers a brief review of preclinical animal models, which are essential tools in the study of tumour immunology and cancer biology, particularly those that recapitulate the chronic nature of host-tumour interactions and help guide the development and testing of new therapies.     

CTLA4 expression is an indicator and regulator of steady-state CD4+ FoxP3+ T cell homeostasis

The presence of FoxP3(+) regulatory T cells (Tregs) is necessary for control of deleterious immune responses in the steady state; however, mechanisms for maintaining the frequency and quality of endogenous Tregs are not well defined. In this study, we used in vivo modulators of the CD28 and CTLA4 pathways administered to intact mice to reveal mechanisms controlling the homeostasis and phenotype of endogenous Tregs. We demonstrate that expression of the negative costimulatory regulator CTLA4 on FoxP3(+) Tregs in vivo is a direct consequence of their rapid, perpetual homeostasis. Up-regulation of CTLA4 expression occurs only on FoxP3(+) Tregs undergoing extensive proliferation and can be abrogated by inhibiting the CD28 pathway, coinciding with a reduction in FoxP3(+) Treg proliferation and frequency. We further demonstrate that CTLA4 negatively regulates steady-state Treg homeostasis, given that inhibiting CTLA4 signaling with an anti-CTLA4 blocking Ab greatly enhances Treg proliferation and overall Treg frequency. Our findings provide new insight into the origin and role of CTLA4 expression on natural FoxP3(+) Tregs and reveal opposing effects of costimulation modulators on the steady-state level and quality of Tregs, with implications regarding their effects on endogenous Tregs in patients receiving immunotherapy.     

Cross-talk between NKT and regulatory T cells (Tregs) in modulation of immune response in patients with colorectal cancer following different pain management techniques

Natural killer T (NKT) and regulatory T cells (Tregs) play an important role in innate immune response. Natural killer (NK) and NKT cells are indispensable factors in the body's ongoing defense against tumor development, as well as viral infection. NKT cells are a subset of T cells that shares properties of natural killer cells and conventional T cells. They are involved in innate immune responses, tumor rejection, post transplantation immunotherapy, immune surveillance and control of autoimmune diseases. They may also play both protective and harmful roles in the progression of certain autoimmune diseases, such as diabetes, lupus, atherosclerosis, and allergen-induced asthma. Immune surveillance involves the process whereby precancerous and malignant cells are recognized by the host immune system as damaged and are consequently targeted for elimination. The pharmacological management of postoperative pain in patients with malignancies uses very different techniques whose possible cytotoxic functions we still known very poor. The present study compared effects of two different postoperative pain management techniques in patients undergoing colorectal cancer surgery on the innate immunity. Our data indicate that the patients with colorectal cancer have significantly increased the percentage of Tregs and NKT cells. The values were statistically higher during epidural analgesia in comparison with intravenous analgesia, indicating that epidural pain management technique ameliorate the immune suppression after surgery.     

Modeling adaptive regulatory T-cell dynamics during early HIV infection

Regulatory T-cells (Tregs) are a subset of CD4(+) T-cells that have been found to suppress the immune response. During HIV viral infection, Treg activity has been observed to have both beneficial and deleterious effects on patient recovery; however, the extent to which this is regulated is poorly understood. We hypothesize that this dichotomy in behavior is attributed to Treg dynamics changing over the course of infection through the proliferation of an 'adaptive' Treg population which targets HIV-specific immune responses. To investigate the role Tregs play in HIV infection, a delay differatial equation model was constructed to examine (1) the possible existence of two distinct Treg populations, normal (nTregs) and adaptive (aTregs), and (2) their respective effects in limiting viral load. Sensitivity analysis was performed to test parameter regimes that show the proportionality of viral load with adaptive regulatory populations and also gave insight into the importance of downregulation of CD4(+) cells by normal Tregs on viral loads. Through the inclusion of Treg populations in the model, a diverse array of viral dynamics was found. Specifically, oscillatory and steady state behaviors were both witnessed and it was seen that the model provided a more accurate depiction of the effector cell population as compared with previous models. Through further studies of adaptive and normal Tregs, improved treatments for HIV can be constructed for patients and the viral mechanisms of infection can be further elucidated.     

Regulatory T cells target chemokine secretion by dendritic cells independently of their capacity to regulate T cell proliferation

The clinical manipulation of regulatory T cells (Tregs) represents a promising strategy for the regulation of unwanted immune responses. It is now becoming clear that Tregs exert multiple effects on different cell targets under particular conditions; however, the interplay between these different factors remains unclear. Using mouse Tregs of known Ag specificity, we report in this study two different levels of Treg-mediated suppression: one that targets T cell proliferation and one that targets dendritic cell-mediated proinflammatory chemokine (CCL3 and CCL4) production. These two effects can be dissociated, and whereas modulation of T cell proliferation depends on the strength of the antigenic stimulus, modulation of chemokine production by dendritic cells does not. We also provide evidence that the bystander effect of Tregs on immune responses observed in vivo may be in great part explained by a decrease in the recruitment of target T cells, and therefore in the magnitude of the response, rather than by a direct effect on their priming or proliferation. Overall, our results shed some light on the different aspects that need to be considered when attempting to modulate Tregs for clinical purposes.     

Cross-presentation of tumour antigens: evaluation of threshold, duration, distribution and regulation

The development of technology to measure antigen presentation in the secondary lymphoid system has provided the opportunity of analysing components of the host antitumour immune response that have, until now, been unavailable for study. In particular, this technology has enabled us to evaluate threshold levels of tumour antigen required for cross-presentation in draining lymph nodes, the duration of this antigen presentation and processes that regulate tumour antigen presentation. Thus, we have been able to dissect out the relationship between antigen presentation and the resultant development of effector function in class I-restricted T cells, as well as the role of regulatory CD4 cells. We have also used this technology to evaluate the effects of antitumour therapy on local antigen cross-presentation.     

FOXP3~+调节性T细胞

调节性T细胞是一类可以调节其他多种免疫细胞功能的T细胞亚型,其正常生理功能对体内免疫稳态维持必不可少。调节性T细胞功能失调与人类多种重大疾病,如自身免疫性疾病、感染性疾病、过敏性疾病、恶性肿瘤、移植排斥的发生、发展及治疗都密切相关。调节性T细胞可分为多种亚型,其中最重要也是目前研究最多的为表达叉头状家族转录因子FOXP3的天然调节性T细胞及诱导调节性T细胞。深入研究FOXP3+调节性T细胞的发育及功能的分子及细胞免疫学机制,将为重大免疫性疾病的临床治疗提供创新性线索。     

Oxygen as a regulator of cellular phenotypes in pregnancy and cancer

Cellular phenotype is determined by genetic and microenvironmental factors. There is evidence that tissue oxygenation status is one of the microenvironmental factors regulating cellular behaviour. Both normal and pathological processes such as blastocyst implantation in the uterus, placentation, and rapidly growing tumours occur under conditions characterized by relatively low oxygen levels. In this review, we address the effects of low oxygen concentrations on the phenotype of trophoblast and cancer cells. We provide evidence that oxygenation levels play an important role in the regulation of normal and pathological cellular invasiveness as it occurs during trophoblast invasion of the uterus and in tumour progression and metastasis, drug resistance in cancer, and antitumour activity of natural killer cells of the immune system.     

Neuropilin 1: function and therapeutic potential in cancer

Neuropilin 1 (NRP1) is a transmembrane glycoprotein that acts as a co-receptor for a number of extracellular ligands including class III/IV semaphorins, certain isoforms of vascular endothelial growth factor and transforming growth factor beta. An exact understanding of the role of NRP1 in the immune system has been obscured by the differences in NRP1 expression observed between mice and humans. In mice, NRP1 is selectively expressed on thymic-derived Tregs and greatly enhances immunosuppressive function. In humans, NRP1 is expressed on plasmacytoid dendritic cells (pDCs) where it aids in priming immune responses and on a subset of T regulatory cells (Tregs) isolated from secondary lymph nodes. Preliminary studies that show NRP1 expression on T cells confers enhanced immunosuppressive activity. However, the mechanism by which this activity is mediated remains unclear. NRP1 expression has also been identified on activated T cells and Tregs isolated from inflammatory microenvironments, suggesting NRP1 might represent a novel T cell activation marker. Of clinical interest, NRP1 may enhance Treg tumour infiltration and a decrease in NRP1+ Tregs correlates with successful chemotherapy, suggesting a specific role for NRP1 in cancer pathology. As a therapeutic target, NRP1 allows simultaneous targeting of NRP1-expressing tumour vasculature, NRP1+ Tregs and pDCs. With the development of anti-NRP1 monoclonal antibodies and cell-penetrating peptides, NRP1 represents a promising new target for cancer therapies. This paper reviews current knowledge on the role and function of NRP1 in Tregs and pDCs, both in physiological and cancer settings, as well as its potential as a therapeutic target in cancer.