Aldehyde dehydrogenase in regulatory T-cell development,immunity and cancer

The role of aldehyde dehydrogenase (ALDH) in carcinogenesis and resistance to cancer therapies is well known. Mounting evidence also suggests a potentially important role for ALDH in the induction and function of regulatory T (Treg) cells. Treg cells are important cells of the immune system involved in promoting immune tolerance and preventing aberrant immune responses to beneficial or non-harmful antigens. However, Treg cells also impair tumor immunity, leading to the progression of various carcinomas. ALDH expression and the subsequent production of retinoic acid by numerous cells, including dendritic cells, macrophages, eosinophils and epithelial cells, seems important in Treg induction and function in multiple organ systems. This is particularly evident in the gastrointestinal tract, pulmonary tract and skin, which are exposed to a myriad of environmental antigens and represent interfaces between the human body and the outside world. Expression of ALDH in Treg cells themselves may also be involved in the proliferation of these cells and resistance to certain cytotoxic therapies. Hence, inhibition of ALDH expression may be useful to treat cancer. Besides the direct effect of ALDH inhibition on carcinogenesis and resistance to cancer therapies, inhibition of ALDH could potentially augment the immune response to tumor antigens by inhibiting Treg induction, function and ability to promote immune tolerance to tumor cells in multiple cancer types.     

T cell responses induced by allergen-specific immunotherapy

Allergen‐specific immunotherapy is recognized as a highly effective practice in the treatment of patients with severe allergic rhinitis and/or asthma and is recommended by World Health Organization as an integrated part of allergy management strategy. Several studies have shown that allergen‐specific immunotherapy, based on the administration of increasing doses of allergen, achieves a hyposensitization and reduces both early and late responses occurring during the natural exposure to the allergen itself. This is the unique antigen‐specific immunomodulatory treatment in current use for human diseases. Successful immunotherapy is associated with reductions in symptoms and medication scores and improved quality of life. After interruption it usually confers long‐term remission of symptoms and prevents the onset of new sensitizations in children up to a number of years. Subcutaneous immunotherapy usually suppresses the allergen‐induced late response in target organs, likely due to the reduction of the infiltration of T cells, eosinophils, basophils, mast cells and neutrophils. In addition to the reduction of cells of allergic inflammation, immunotherapy also decreases inflammatory mediators at the site of allergen exposure. This review provides an update on the immunological T cell responses induced by conventional subcutaneous and sublingual immunotherapy, and gives a unifying view to reconciling the old dualism between immunoredirecting and immunoregulating mechanisms.     

Regulatory T cells in ovarian cancer: biology and therapeutic potential

Tumors express tumor-associated antigens (TAA) and thus should be the object of immune attack. Nonetheless, spontaneous clearance of established tumors is rare. Much work has demonstrated that tumors have numerous strategies either to prevent presentation of TAA, or to prevent TAA presentation in the context of T-cell co-signaling molecules. Thus, it was thought that lack of TAA-specific immunity was largely a passive process: tumors simply did not present enough TAA, or antigen-presenting cells did not have sufficient stimulatory capacity. On this basis, attempts were made to bolster TAA-specific immunity by using optimal antigen-presenting cells or by growing TAA-specific effector T cells ex vivo followed by adoptive transfer. These approaches met with some success in mouse models of human tumors, and showed some early clinical efficacy in human trials, although long-term efficacy remains to be established, and logistical problems are considerable. These studies established the concept that experimentally induced TAA-specific immunity is a rational and potentially efficacious means to treat cancer, including ovarian cancer. Nonetheless, recent work demonstrates that lack of naturally induced TAA-specific immunity is not simply a passive process. We discuss recent data clearly demonstrating that 'tumors actively prevent induction of TAA-specific immunity through induction of TAA-specific tolerance'. This tolerance is mediated in part by regulatory T cells (Tregs). Means to revert these tolerizing conditions represent a novel anticancer therapeutic stratagem. We discuss Tregs in this regard in human ovarian cancer and present evidence that depleting Treg in human cancer, including ovarian cancer, using denileukin diftitox (Ontak), improves immunity and may be therapeutic.     

Distinct subpopulations of epithelial ovarian cancer cells can differentially induce macrophages and T regulatory cells toward a pro-tumor phenotype

Citation Alvero AB, Montagna MK, Craveiro V, Liu L, Mor G. Distinct subpopulations of epithelial ovarian cancer cells can differentially induce macrophages and T regulatory cells toward a pro‐tumor phenotype. Am J Reprod Immunol 2012; 67: 256–265 Problem Presence of immune infiltrates in the tumor does not always correlate with an anti‐tumoral immune response. We previously identified two subpopulations of epithelial ovarian cancer (EOC) cells with differential cytokine profile. We hypothesize that these two subpopulations of EOC cells may differentially regulate the immune phenotype in the tumor microenvironment and therefore affect the immune response. Method of Study Macrophages derived from CD14+ monocytes and naive CD4+T cells were treated with conditioned media from two subpopulations of EOC cells. Differentiation markers and phagocytic activity were measured by western blot analysis and flow cytometry. Cytokine levels were quantified using xMAP technology. Results Type I EOC cells are able to enhance macrophages’ capacity for tumor repair and renewal by enhancing expression of scavenger receptors and by promoting the secretion of cytokines associated with tissue repair. On the other hand, type II EOC cells are able to create a tolerant microenvironment and prevent an immune response by inducing macrophages’ to secrete IL‐10 and by promoting the generation of T regs. Conclusion We demonstrate that each ovarian cancer cell subpopulation can induce a unique phenotype of macrophages and T cells, both associated with tumor‐supportive function.     

Minireview: Regulatory T Cells and Ovarian Cancer

ABSTRACT

In the last 15 years, it has become apparent that ovarian cancer is recognized by the immune system, taking into account that T cell infiltration can be associated with increased overall survival. Several studies indicate that a correct combination of cluster of differentiation 8 and cluster of differentiation 4 T cells is key to fight tumor progression and that the presence of regulatory T cells (Tregs) infiltrating ovarian solid tumors (or present in ascites) is deleterious. Several markers that characterize Tregs include glucocorticoid-induced tumor necrosis factor receptor, cytotoxic T lymphocyte antigen-4, and forkhead box protein 3 (Foxp3). Research has shown that Tregs can infiltrate cancerous tissue and contribute to tumor growth by secreting immunosuppressive cytokines such as transforming growth factor beta and interleukin (IL)-10. Importantly, these cells might hamper the efficacy of immunotherapeutic approaches, thus strategies involving depletion or regulation of this population have been proposed and tested in experimental models. In this Minireview, we will discuss the relevance of Tregs in ovarian cancer and the experimental approaches destined to impair their immunosuppressive effects.     

Cancer vaccines for established cancer: how to make them better?

Summary: If one envisions dendritic cells (DCs) as nature's adjuvant, then it is easy to predict that they would be advantageous for cancer immunotherapy. Advances in culture processes that generate large numbers of purified and functionally mature DCs raised the possibility that DCs might be promising clinical agents to generate effective immune responses against cancer. The use of mature DCs as cellular vaccines was proposed to be superior to conventional strategies aimed at treating cancer, yet a phase III clinical trial in patients with melanoma demonstrated no increased benefit of DCs over standard therapy. Despite this and other apparent failures, we propose that DC-based therapy should not be discarded but rather reassessed. The heterogeneity of DCs and their interaction with other innate cells and regulatory and effector pathways must be clearly understood before the full therapeutic benefit of DCs are recognized. Several aspects of DC vaccination require optimization including the following: effective delivery of vaccines to DCs in lymphoid tissues; incorporation of components that induce appropriate DC activation; and facilitation of innate and adaptive interactions and reduction of regulatory T-cell networks or suppressive microenvironments that hinder the function of immune effectors. Application of this knowledge is resulting in encouraging new data in pre-clinical settings, where multiple arms of the immune system are targeted for cancer therapy.     

HE4 suppresses the expression of osteopontin in mononuclear cells and compromises their cytotoxicity against ovarian cancer cells

Ovarian cancers are known to evade immunosurveillance and to orchestrate a suppressive immune microenvironment. Here we examine the role of human epididymis protein 4 (HE4), an ovarian cancer biomarker, in immune evasion. Through modified subtractive hybridization analyses we have characterized the gene targets of HE4 in human peripheral blood mononuclear cells (PBMCs), and established a preliminary mechanism for HE4‐mediated immune failure in ovarian tumours. Upon exposure of purified PMBCs to HE4, osteopontin (OPN) and dual‐specificity phosphatase 6 (DUSP6) emerged as the most suppressed and up‐regulated genes, respectively. SKOV3 and OVCAR8, human ovarian carcinoma cell lines, exhibited enhanced proliferation in conditioned media from HE4‐exposed PBMCs, an effect that was attenuated by the addition of recombinant OPN or OPN‐inducible cytokines [interleukin (IL)‐12 and interferon (IFN)‐?]. Additionally, upon co‐culture with PBMCs, HE4‐silenced SKOV3 cells were found to be more susceptible to cytotoxic cell death. The relationship between HE4 and OPN was reinforced further through the analysis of serous ovarian cancer patient samples. In these biopsy specimens, the number of OPN⁺ T cells correlated positively with progression free survival (PFS) and inversely with serum HE4 level. Taken together, these findings show that HE4 enhances ovarian cancer tumorigenesis by compromising OPN‐mediated T cell activation.     

Adaptive immunity programmes in breast cancer

The role of the immune system in shaping cancer development and patient prognosis has recently become an area of intense focus in industry and academia. Harnessing the adaptive arm of the immune system for tumour eradication has shown great promise in a variety of tumour types. Differences between tissues, however, necessitate a greater understanding of the adaptive immunity programmes that are active within each tumour type. In breast cancer, adaptive immune programmes play diverse roles depending on the cellular infiltration found in each tumour. Cytotoxic T lymphocytes and T helper type 1 cells can induce tumour eradication, whereas regulatory T cells and T helper type 2 cells are known to be involved in tumour‐promoting immunosuppressive responses. Complicating these matters, heterogeneous expression of hormone receptors and growth factors in different tumours leads to disparate, patient‐specific adaptive immune responses. Despite this non‐conformity in adaptive immune behaviours, encouraging basic and clinical results have been observed that suggest a role for immunotherapeutic approaches in breast cancer. Here, we review the literature pertaining to the adaptive immune response in breast cancer, summarize the primary findings relating to the breast tumour's biology, and discuss potential clinical immunotherapies.     

Immunotherapies based on PD-1/PD-L1 pathway inhibitors in ovarian cancer treatment

Immunotherapies based on anti-programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway inhibitors may turn out effective in ovarian cancer (OC) treatment. They can be used in combination with standard therapy and are especially promising in recurrent and platinum-resistant OC. There is growing evidence that the mechanism of the PD-1/PD-L1 pathway can be specific for a particular histological cancer type. Interestingly, the data have shown that the PD-1/PD-L1 pathway blockade may be effective, especially in the endometrioid type of OC. It is important to identify the cause of anti-tumor immune response suppression and exclude its other mechanisms in OC patients. It is also necessary to conduct subsequent studies to confirm in which OC cases the treatment is effective and how to select patients and combine drugs to improve patient survival.     

The role of physiological self-antigen in the acquisition and maintenance of regulatory T-cell function

Summary: The CD4⁺CD25⁺ regulatory T cells (Tregs) are efficient regulators of autoimmunity, but the mechanism remains elusive. We summarize recent data for the conclusion that disease‐specific Tregs respond to tissue antigens to maintain physiological tolerance and prevent autoimmunity. First, polyclonal Tregs from antigen‐positive donors suppress autoimmune ovarian disease (AOD) or experimental autoimmune prostatitis in day 3 thymectomized (d3tx) mice more efficiently than Tregs from antigen‐negative donors. Second, Tregs of antigen‐negative adult mice respond to cognate antigen in vivo and rapidly gain disease‐specific Treg function. Third, in d3tx female recipients devoid of neonatal ovarian antigens, only female Tregs suppressed AOD; the male Tregs gain AOD‐suppressing function by responding to the ovarian antigen in the recipients and mask the supremacy of female Tregs in AOD suppression. Fourth, when Tregs completely suppress AOD, the ovary‐draining lymph node is the only location with evidence of profound and persistent (but reversible) host T‐cell suppression. Fifth, from these nodes, highly potent AOD‐suppressing Tregs are retrievable. We conclude that self‐tolerance involves the continuous priming of Tregs by autoantigens, and in autoimmune disease suppression, the effector T‐cell response is continuously negated by potent disease‐specific Tregs that accumulate at the site of autoantigen presentation.     

Targeting cytokines secreted by CD4+CD25highCD127low regulatory T cells inhibits ovarian cancer progression

Epithelial ovarian cancer (EOC) is one of the major malignant cancers with high rates of early metastasis in which regulatory T cells (Tregs) play an important role. Tregs suppress immune responses and promote the development of tumours in patients with EOC. However, the underlying mechanisms remain unclear. In this study, we found higher levels of CD4⁺CD25^highCD127^low Tregs in patients with EOC than in patients with benign ovarian tumours and healthy donors. The immune inhibitory effect of Tregs functions by maintaining high levels of immunosuppressive cytokines in EOC. The high levels of Tregs and related cytokines (TGF‐β1 or IL‐10) were associated with lymphatic metastasis and FIGO stages of patients with EOC. Expression of matrix metalloproteinase (MMP)‐2 and tissue inhibitors of metalloproteinase (TIMP)‐2 in EOC cell lines were significantly regulated in the coculture experiment with CD4⁺CD25^highCD127^low Tregs sorted from EOC patients. Levels of MMP‐2 and TIMP‐2 conversely changed after blocking IL‐10R and TGF‐β1R in EOC cells. The invasion ability of EOC cells was also significantly downregulated in this process. The metastasis of EOC cells was correlated with the levels of TGF‐β1 or IL‐10. These findings suggested that immunosuppressive cytokines secreted by CD4⁺ Tregs could be a novel target for inhibiting EOC progression.     

Regulatory T Cells and Cancer: A Two-Sided Story

ABSTRACT

Regulatory T cells (Tregs) play pivotal roles in limiting the duration and magnitude of immune response against infectious agents and self-antigens. This is accomplished through contact-dependent and -independent mechanisms that involve crosstalk between Treg cells and other immune and tissue-specific cell types. The same machinery is employed by Tregs to regulate immune responses to cancer, limiting both pro-tumor inflammation and anti-tumor immunity. Factors produced by Treg cells also act directly on transformed epithelial cells and exert opposing effects during different stages of cancer development. Therefore, the immune regulatory cell population serves as a double-edged sword for the development, progression, and treatment of cancers. In this review, we summarize current knowledge on the roles of Treg lymphocytes during cancer development, as well as the underlying cellular and molecular mechanism.     

Intratumoral regulatory T cells: markers,subsets and their impact on anti-tumor immunity

Regulatory T (Treg) cells play a crucial role in maintaining self-tolerance and resolution of immune responses by employing multifaceted immunoregulatory mechanisms. However, Treg cells readily infiltrate into the tumor microenvironment (TME) and dampen anti-tumor immune responses, thereby becoming a barrier to effective cancer immunotherapy. There has been a substantial expansion in the development of novel immunotherapies targeting various inhibitory receptors (IRs), such as CTLA4, PD1 and LAG3, but these approaches have mechanistically focused on the elicitation of anti-tumor responses. However, enhanced inflammation in the TME could also play a detrimental role by facilitating the recruitment, stability and function of Treg cells by up-regulating chemokines that promote Treg cell migration, and/or increasing inhibitory cytokine production. Furthermore, IR blockade may enhance Treg cell function and survival, thereby serving as a resistance mechanism against effective immunotherapy. Given that Treg cells are comprised of functionally and phenotypically heterogeneous sub-populations that may alter their characteristics in a context-dependent manner, it is critical to identify unique molecular pathways that are preferentially used by intratumoral Treg cells. In this review, we discuss markers that serve to identify certain Treg cell subsets, distinguished by chemokine receptors, IRs and cytokines that facilitate their migration, stability and function in the TME. We also discuss how these Treg cell subsets correlate with the clinical outcome of patients with various types of cancer and how they may serve as potential TME-specific targets for novel cancer immunotherapies.     

溶血磷脂酸与卵巢肿瘤

溶血磷脂酸是一种具有细胞间信号传导作用的脂类小分子物质，具有广泛的生物学效应。研究发现卵巢癌患者的腹水中存在溶血磷脂酸，它可以促进癌细胞的生长；卵巢癌患者的血浆中具有明显高于正常对照组的溶血磷脂酸，用于卵巢癌的诊断具有较高的敏感性及特异性。优于Ca125。卵巢癌的细胞呆分泌溶血磷脂酸，且细胞中存在溶血磷脂酸的自分泌环，它与肿瘤的发展，耐药及预后密切相关。这将对卵巢癌的治疗提供新的可能。     

CD8+ T cell exhaustion in anti-tumour immunity: The new insights for cancer immunotherapy

CD8⁺ T cells play a crucial role in anti-tumour immunity, but they often undergo exhaustion, which affects the anti-tumour activity of CD8⁺ T cells. The effect and mechanism of exhausted CD8⁺ T cells have become the focus of anti-tumour immunity research. Recently, a large number of studies have confirmed that long-term antigen exposure can induce exhaustion. Cytokines previously have identified their effects (such as IL-2 and IL-10) may play a dual role in the exhaustion process of CD8⁺ T cells, suggesting a new mechanism of inducing exhaustion. This review just focuses our current understanding of the biology of exhausted CD8⁺ T cells, including differentiation pathways, cellular characteristics and signalling pathways involved in inducing exhaustion, and summarizes how these can be applied to tumour immunotherapy.     

Interleukin-2 in the development and control of inflammatory disease

Summary: Interleukin-2 (IL-2) has multiple, sometimes opposing, functions during an inflammatory response. It is a potent inducer of T-cell proliferation and T-helper 1 (Th1) and Th2 effector T-cell differentiation and provides T cells with a long-lasting competitive advantage resulting in the optimal survival and function of memory cells. In a regulatory role, IL-2 is important for the development, survival, and function of regulatory T cells, it enhances Fas-mediated activation-induced cell death, and it inhibits the development of inflammatory Th17 cells. Thus, in its dual and contrasting functions, IL-2 contributes to both the induction and the termination of inflammatory immune responses.     

Nature of tumour rejection antigens in ovarian cancer

Major progress in the analysis of human immune responses to cancer has been made through the molecular characterization of human tumour antigens. The development of therapeutic strategies for eliciting immune‐mediated rejection of tumours has accelerated due to the elucidation of the molecular basis for tumour cell recognition and destruction by immune cells. Of the various human tumour antigens defined to date in ovarian cancer, the cancer‐testis (CT) family of antigens have been studied extensively preclinically and clinically because of their testis‐restricted expression in normal tissues and ability to elicit robust immune responses. Recent developments in cancer sequencing technologies offer a unique opportunity to identify tumour mutations with the highest likelihood of being expressed and recognized by the immune system. Such mutations, or neoantigens, could potentially serve as specific immune targets for T‐cell‐mediated destruction of cancer cells. This review will highlight current work in selecting tumour rejection antigens in ovarian cancer for improving the efficacy of immunotherapy.     

年轻早期子宫内膜癌患者保留卵巢的安全性及预后

目的探讨年轻的I期子宫内膜癌患者保留卵巢的安全性及预后。方法回顾性分析北京协和医院2005年1月至2011年12月间接受手术治疗的年龄≤45岁的I期子宫内膜癌患者的临床病理资料。根据术中是否保留卵巢分为保留卵巢组和切除卵巢组,比较分析两组的临床病理特征及预后。结果研究共纳入患者72例,其中保留卵巢组25例(34.7%),切除卵巢组47例(65.3%)。保留卵巢组患者与切除卵巢组患者相比更年轻(P=0.007),并且接受淋巴结切除的比例明显低于保留卵巢组患者(P0.001)。两组患者在分期、肿瘤分级、肌层浸润深度以及术后辅助治疗方面均无统计学差异(P0.05)。72例患者的中位随诊时间为89个月(7~131月),共有5例患者复发,没有患者死亡。Kaplan-Meier生存曲线及log rank检验显示两组的无复发生存时间无差异(P=0.194)。COX风险回归分析发现保留卵巢对无复发生存期无影响(HR=3.08,95%CI 0.54~18.44)。结论年轻的早期子宫内膜癌患者保留卵巢是安全的,对患者的无复发生存时间无显著影响。