Focus on mast cells in the tumor microenvironment: Current knowledge and future directions

Mast cells (MCs) are crucial cells participating in both innate and adaptive immune processes that play important roles in protecting human health and in the pathophysiology of various diseases, such as allergies, cardiovascular diseases, and autoimmune diseases. In the context of tumors, MCs are a non-negligible population of immune cells in the tumor microenvironment (TME). In most tumor types, MCs accumulate in both the tumor tissue and the surrounding tissue. MCs interact with multiple components of the TME, affecting TME remodeling and the tumor cell fate. However, controversy persists regarding whether MCs contribute to tumor progression or trigger an anti-tumor immune response. This review focuses on the context of the TME to explore the specific properties and functions of MCs and discusses the crosstalk that occurs between MCs and other components of the TME, which affect tumor angiogenesis and lymphangiogenesis, invasion and metastasis, and tumor immunity through different mechanisms. We also anticipate the potential role of MCs in cancer immunotherapy, which might expand upon the success achieved with existing cancer therapies.     

Regulatory B cells and T cell Regulation in Cancer

Recent researches shed light on B cell role on various autoimmune diseases, including autoantibody-mediated diseases as well as T cell-mediated autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. B cells play a critical role in the immune response beyond the production of antibodies through mechanisms such as antigen presentation and cytokine production. Furthermore, B cells have recently been recognized to play a role in promoting tumor immunity against cancer. However, not all B cells positively regulate immune responses. Regulatory B cells negatively regulate immune responses by the production of anti-inflammatory cytokines such as interleukin (IL)-10, IL-35, and transforming growth factor-beta. Thus, a balance between effector and regulatory B cells regulates the immune response through the release of cytokines. In this review, we highlight the main emerging roles of B cells in tumor immunity with a focus on the T cell response. These findings can guide a protocol for selectively depleting regulatory B cells as a potential therapeutic strategy for patients with cancer.     

Oncolytic Immunotherapy: Can’t Start a Fire Without a Spark

Recent advances in cancer immunotherapy have renewed interest in oncolytic viruses (OVs) as a synergistic platform for the development of novel antitumor strategies. Cancer cells adopt multiple mechanisms to evade and suppress antitumor immune responses, essentially establishing a non-immunogenic (‘cold’) tumor microenvironment (TME), with poor T-cell infiltration and low mutational burden. Limitations to the efficacy of immunotherapy still exist, especially for a variety of solid tumors, where new approaches are necessary to overcome physical barriers in the TME and to mitigate adverse effects associated with current immunotherapeutics. OVs offer an attractive alternative by inducing direct oncolysis, immunogenic cell death, and immune stimulation. These multimodal mechanisms make OVs well suited to reprogram non-immunogenic tumors and TME into inflamed, immunogenic (‘hot’) tumors; enhanced release of tumor antigens by dying cancer cells is expected to augment T-cell infiltration, thereby eliciting potent antitumor immunity. Advances in virus engineering and understanding of tumor biology have allowed the optimization of OV-tumor selectivity, oncolytic potency, and immune stimulation. However, OV antitumor activity is likely to achieve its greatest potential as part of combinatorial strategies with other immune or cancer therapeutics.     

The roles of mast cells in anticancer immunity

The tumor microenvironment (TME), which is composed of stromal cells such as endothelial cells, fibroblasts, and immune cells, provides a supportive niche promoting the growth and invasion of tumors. The TME also raises an immunosuppressive barrier to effective antitumor immune responses and is therefore emerging as a target for cancer immunotherapies. Mast cells (MCs) accumulate in the TME at early stages, and their presence in the TME is associated with poor prognosis in many aggressive human cancers. Some well-established roles of MCs in cancer are promoting angiogenesis and tumor invasion into surrounding tissues. Several mouse models of inducible and spontaneous cancer show that MCs are among the first immune cells to accumulate within and shape the TME. Although MCs and other suppressive myeloid cells are associated with poor prognosis in human cancers, high densities of intratumoral T effector (T(eff)) cells are associated with a favorable prognosis. The latter finding has stimulated interest in developing therapies to increase intratumoral T cell density. However, cellular and molecular mechanisms promoting high densities of intratumoral T(eff) cells within the TME are poorly understood. New evidence suggests that MCs are essential for shaping the immune-suppressive TME and impairing both antitumor T(eff) cell responses and intratumoral T cell accumulation. These roles for MCs warrant further elucidation in order to improve antitumor immunity. Here, we will summarize clinical studies of the prognostic significance of MCs within the TME in human cancers, as well as studies in mouse models of cancer that reveal how MCs are recruited to the TME and how MCs facilitate tumor growth. Also, we will summarize our recent studies indicating that MCs impair generation of protective antitumor T cell responses and accumulation of intratumoral T(eff) cells. We will also highlight some approaches to target MCs in the TME in order to unleash antitumor cytotoxicity.     

Intratumoral lipid metabolic reprogramming as a pro-tumoral regulator in the tumor milieu

Reprogramming of the tumor microenvironment (TME) is a hallmark of cancer. Metabolic reprogramming is a vital approach to sustaining the energy supply in the TME. This alteration exists in both cancer cells and TME cells, collectively establishing an immunotolerant niche to facilitate tumor progression. Limited resources lead to metabolic competition and hinder the biological functions of anti-tumoral immunity. Reprogramming of lipid metabolism and tumor progression is closely related to each other. Due to the complexity of fatty acid (FA) types and the lack of an effective approach for detection, the mechanisms and effects of FA metabolic reprogramming have been unclear. Herein, we review FA metabolism in the tumor milieu, summarize how FA metabolic reprogramming influences antitumor immune response, suggest the mechanisms by which FAs affect immunotherapy against cancer, and discuss the potential of FA metabolism-based drugs in cancer treatment.     

Effect of mesenchymal stem cells-derived exosomes on tumor microenvironment: Tumor progression versus tumor suppression

Mesenchymal stem cells (MSCs) are multipotent cells with the potential to differentiate into different cell types. Owing to their immunosuppressive and anti-inflammatory properties, they are widely used in regenerative medicine, but they have a dual effect on cancer progression and exert both growth-stimulatory or -inhibitory effects on different cancer types. It has been proposed that these controversial effects of MSC in tumor microenvironment (TME) are mediated by their polarization to proinflammatory or anti-inflammatory phenotype. In addition, they can polarize the immune system cells that in turn influence tumor progression. One of the mechanisms involved in the TME communications is extracellular vesicles (EVs). MSCs, as one of cell populations in TME, produce a large amount of EVs that can influence tumor development. Similar to MSC, MSC-EVs can exert both anti- or protumorigenic effects. In the current study, we will investigate the current knowledge related to MSC role in cancer progression with a focus on the MSC-EV content in limiting tumor growth, angiogenesis, and metastasis. We suppose MSC-EVs can be used as safe vehicles for delivering antitumor agents to TME.     

Activation of fibroblasts in cancer stroma

Tumor microenvironment has emerged as an important target for cancer therapy. In particular, cancer-associated fibroblasts (CAF) seem to regulate many aspects of tumorigenesis. CAFs secrete a variety of soluble factors that act in a paracrine manner and thus affect not only cancer cells, but also other cell types present in the tumor stroma. Acting on cancer cells, CAFs promote tumor growth and invasion. They also enhance angiogenesis by secreting factors that activate endothelial cells and pericytes. Tumor immunity is mediated via cytokines secreted by immune cells and CAFs. Both immune cells and CAFs can exert tumor-suppressing and -promoting effects. CAFs, and the factors they produce, are attractive targets for cancer therapy, and they have proven to be useful as prognostic markers. In this review we focus mainly on carcinomas and discuss the recent findings regarding the role of activated fibroblasts in driving tumor progression.     

中性粒细胞在抗结核免疫中的作用

结核病是世界范围内的重要传染性疾病之一,严重威胁人类健康。免疫细胞在抗结核免疫过程中起重要作用,各细胞亚群通过不同作用机制影响结核病的病程及转归。中性粒细胞为机体应对结核分枝杆菌感染的第一道防线,在宿主免疫应答过程中是一把双刃剑。一方面,机体感染结核分枝杆菌后,中性粒细胞于第一时间向感染部位聚集,通过多种方式对抗感染：中性粒细胞吞噬结核分枝杆菌后,通过自身凋亡而杀菌;参与形成肉芽肿,形成胞外陷阱来限制结核分枝杆菌的生长和传播;产生功能性细胞因子,调控宿主的抗结核免疫反应。另一方面,中性粒细胞还参与机体的病理损伤过程,甚至促进体内结核分枝杆菌的生长。本文综述了中性粒细胞在抗结核免疫中作用的最新研究进展。     

Extracellular vesicle-orchestrated crosstalk between cancer-associated fibroblasts and tumors

Communication networks in the tumor microenvironment (TME) play a crucial role in tumor progression. Cancer-associated fibroblasts (CAFs) are among the most abundant stromal cells in the TME. Bidirectional signal transduction between cancer cells and CAFs within the TME is important for cancer development and treatment responsiveness. Extracellular vesicles (EVs) carrying proteins, miRNAs, and other biomolecules are secreted into the extracellular matrix (ECM), which has been demonstrated to be an important communication medium between tumors and CAFs. Tumors regulate the activation of CAFs by secreting EVs. Conversely, CAFs can also affect tumor proliferation, metastasis, and therapeutic resistance through EVs. Here, we will classify EV cargoes and discuss the role of EV-mediated interactions between CAFs and tumors, reviewing current knowledge in combination with our confirmed results.     

Extracellular vesicle-orchestrated crosstalk between cancer-associated fibroblasts and tumors

Communication networks in the tumor microenvironment (TME) play a crucial role in tumor progression. Cancer-associated fibroblasts (CAFs) are among the most abundant stromal cells in the TME. Bidirectional signal transduction between cancer cells and CAFs within the TME is important for cancer development and treatment responsiveness. Extracellular vesicles (EVs) carrying proteins, miRNAs, and other biomolecules are secreted into the extracellular matrix (ECM), which has been demonstrated to be an important communication medium between tumors and CAFs. Tumors regulate the activation of CAFs by secreting EVs. Conversely, CAFs can also affect tumor proliferation, metastasis, and therapeutic resistance through EVs. Here, we will classify EV cargoes and discuss the role of EV-mediated interactions between CAFs and tumors, reviewing current knowledge in combination with our confirmed results.     

Emerging role of metabolic reprogramming in tumor immune evasion and immunotherapy

Mounting evidence has revealed that the therapeutic efficacy of immunotherapies is restricted to a small portion of cancer patients. A deeper understanding of how metabolic reprogramming in the tumor microenvironment(TME) regulates immunity remains a major challenge to tumor eradication. It has been suggested that metabolic reprogramming in the TME may affect metabolism in immune cells and subsequently suppress immune function. Tumor cells compete with infiltrating immune cells for nutrients and metabolites. Notably, the immunosuppressive TME is characterized by catabolic and anabolic processes that are critical for immune cell function, and elevated inhibitory signals may favor cancer immune evasion. The major energy sources that supply different immune cell subtypes also undergo reprogramming. We herein summarize the metabolic remodeling in tumor cells and different immune cell subtypes and the latest advances underlying the use of metabolic checkpoints in antitumor immunotherapies. In this context, targeting both tumor and immune cell metabolic reprogramming may enhance therapeutic efficacy.     

Empowering dendritic cell cancer vaccination: the role of combinatorial strategies

Dendritic cells (DCs) are bone marrow–derived immune cells that play a crucial role in inducing the adaptive immunity and supporting the innate immune response independently from T cells. In the last decade, DCs have become a hopeful instrument for cancer vaccines that aims at re-educating the immune system, leading to a potent anti-cancer immune response able to overcome the immunosuppressive tumor microenvironment (TME). Although several studies have indicated that DC-based vaccines are feasible and safe, the clinical advantages of DC vaccination as monotherapy for most of the neoplasms remain a distant target. Recently, many reports and clinical trials have widely used innovative combinatorial therapeutic strategies to normalize the immune function in the TME and synergistically enhance DC function. This review will describe the most relevant and updated evidence of the anti-cancer combinatorial approaches to boost the clinical potency of DC-based vaccines.     

Isolation of immune cells from primary tumors

Tumors create a unique immunosuppressive microenvironment (tumor microenvironment, TME) whereby leukocytes are recruited into the tumor by various chemokines and growth factors. However, once in the TME, these cells lose the ability to promote anti-tumor immunity and begin to support tumor growth and down-regulate anti-tumor immune responses. Studies on tumor-associated leukocytes have mainly focused on cells isolated from tumor-draining lymph nodes or spleen due to the inherent difficulties in obtaining sufficient cell numbers and purity from the primary tumor. While identifying the mechanisms of cell activation and trafficking through the lymphatic system of tumor bearing mice is important and may give insight to the kinetics of immune responses to cancer, in our experience, many leukocytes, including dendritic cells (DCs), in tumor-draining lymph nodes have a different phenotype than those that infiltrate tumors. Furthermore, we have previously demonstrated that adoptively-transferred T cells isolated from the tumor-draining lymph nodes are not tolerized and are capable of responding to secondary stimulation in vitro unlike T cells isolated from the TME, which are tolerized and incapable of proliferation or cytokine production. Interestingly, we have shown that changing the tumor microenvironment, such as providing CD4(+) T helper cells via adoptive transfer, promotes CD8(+) T cells to maintain pro-inflammatory effector functions. The results from each of the previously mentioned studies demonstrate the importance of measuring cellular responses from TME-infiltrating immune cells as opposed to cells that remain in the periphery. To study the function of immune cells which infiltrate tumors using the Miltenyi Biotech isolation system, we have modified and optimized this antibody-based isolation procedure to obtain highly enriched populations of antigen presenting cells and tumor antigen-specific cytotoxic T lymphocytes. The protocol includes a detailed dissection of murine prostate tissue from a spontaneous prostate tumor model (TRansgenic Adenocarcinoma of the Mouse Prostate -TRAMP) and a subcutaneous melanoma (B16) tumor model followed by subsequent purification of various leukocyte populations.     

Molecular requirements for CD8-mediated rejection of a MUC1-expressing pancreatic carcinoma: implications for tumor vaccines

Previous studies have indicated that different effector cells are required to eliminate MUC1-expressing tumors derived from different organ sites and that different vaccine strategies may be necessary to generate these two different MUC1-specific immune responses. In this study, we characterized molecular components that are required to produce immune responses that eliminate Panc02.MUC1 tumors in vivo by utilizing mice genetically deficient in molecules related to immunity. A parallel study has been reported for a B16.MUC1 tumor model. We confirmed that a CD8(+) effector cell was required to eliminate MUC1-expressing Panc02 tumors, and demonstrated that T cells expressing TCR-alpha/beta and co-stimulation through CD28 and CD40:CD40L interactions played critical roles during the initiation of the anti-Panc02.MUC1 immune response. TCR-alpha/beta(+) cells were required to eliminate Panc02.MUC1 tumors, while TCR-gamma/delta(+) cells played a suppressive non-MUC1-specific role in anti-Panc02 tumor immunity. Type 1 cytokine interferon-gamma (IFN-gamma), but not interleukin-12 (IL-12), was essential for eliminating MUC1-expressing tumors, while neither IL-4 nor IL-10 (type 2 cytokines) were required for tumor rejection. In vitro studies demonstrated that IFN-gamma upregulated MHC class I, but not MHC class II, on Panc02.MUC1 tumor cells. Surprisingly, both perforin and FasL played unique roles during the effector phase of immunity to Panc02.MUC1, while lymphotoxin-alpha, but not TNFR-1, was required for immunity against Panc02.MUC1 tumors. The findings presented here and in parallel studies of B16.MUC1 immunity clearly demonstrate that different effector cells and cytolytic mechanisms are required to eliminate MUC1-expressing tumors derived from different organ sites, and provide insight into the immune components required to eliminate tumors expressing the same antigen but derived from different tissues.     

The anti-tumor activity of IL-12: mechanisms of innate immunity that are model and dose dependent

IL-12 has been demonstrated to have potent anti-tumor activities in a variety of mouse tumor models, but the relative roles of NK, NKT, and T cells and their effector mechanisms in these responses have not been fully addressed. Using a spectrum of gene-targeted or Ab-treated mice we have shown that for any particular tumor model the effector mechanisms downstream of IL-12 often mimic the natural immune response to that tumor. For example, metastasis of the MHC class I-deficient lymphoma, EL4-S3, was strictly controlled by NK cells using perforin either naturally or following therapy with high-dose IL-12. Intriguingly, in B16F10 and RM-1 tumor models both NK and NKT cells contribute to natural protection from tumor metastasis. In these models, a lower dose of IL-12 or delayed administration of IL-12 dictated a greater relative role of NKT cells in immune protection from tumor metastasis. Overall, both NK and NKT cells can contribute to natural and IL-12-induced immunity against tumors, and the relative role of each population is tumor and therapy dependent.     

磷酸酶在病原菌侵染寄主中的作用

磷酸酶不仅在生物体正常细胞进程中具有重要作用,而且在病原菌与寄主相互作用中也起着至关重要的作用。目前,国内外在革兰氏阴性病原菌通过其Ⅲ型分泌系统(Type III secretion system,TTSS)分泌磷酸酶到寄主细胞以调控寄主免疫和扩大病原性方面研究较多,而在病原真菌逃避寄主免疫方面则报道很少。本课题组研究发现昆虫病原真菌绿僵菌分泌的一种胞外酪氨酸蛋白磷酸酶在体外能特异地使蝗虫体液免疫信号转导物质去磷酸化,暗示可能影响蝗虫的免疫防御。以下着重从磷酸酶的分类及其在病原菌侵染寄主中的作用研究等方面进行综述,以期为进一步研究磷酸酶的作用提供参考。     

Tumor Microenvironment and its Implications for Antitumor Immunity in Cholangiocarcinoma: Future Perspectives for Novel Therapies

The incidence of cholangiocarcinoma (CCA) has been increasing over the past few years. Although there are surgery, chemotherapy and other conventional treatment methods, the effect is not as expected. At present, immunotherapy has become the research frontier of cancer treatment, and CCA tumor microenvironment (TME) is becoming a hot exploration direction of immunobiology. TME can affect tumor progression through changes in metabolism, secretion and immunity. Accordingly, understanding the role played by immune cells and stromal cells in TME is important for the study of CCA immunotherapy. This review will discuss the interactions between immune cells (including CD8⁺ T cells, CD4⁺ T cells, macrophages, natural killer cells, dendritic cells, myeloid suppressor cells, mast cells, and neutrophils) and stromal cells (including cancer-associated fibroblasts, endothelial cells) in the TME of CCA. In addition, we will also discuss current research results on TME of CCA and recent advances in immunotherapy.     

恒定自然杀伤T细胞与肿瘤免疫治疗

恒定自然杀伤T细胞(iNKT)是T淋巴细胞的一个独特亚群,兼具自然杀伤(NK)细胞和T细胞特征,同时表达T细胞受体(TCR)和NK细胞表面标志。iNKT细胞被激活后,通过分泌细胞因子,活化其它免疫细胞参与先天性免疫和获得性免疫,在抗肿瘤免疫过程中发挥调节作用。在多种癌症患者体内,发现外周血中iNKT细胞的数量降低、功能减弱,进而导致临床治疗效果不佳。近年来,基础研究和早期临床试验结果表明,注射抗原递呈细胞或/和体外培养并活化的iNKT细胞,抗肿瘤免疫治疗效果显著。本文就iNKT细胞的分类及生物学特性,在肿瘤免疫治疗中的作用与其机制,以及其临床应用等进行综述。