骨髓源性抑制细胞在肿瘤免疫治疗中的研究进展及与肺癌预后的关系

免疫治疗是肺癌新兴治疗方法,其疗效受肿瘤免疫微环境（tumor immune microenvironment,TIME）影响。骨髓源性抑制细胞(myeloid-derived suppressor cells,MDSCs)是免疫微环境的主要免疫抑制细胞,在肿瘤的发生、发展、侵袭和转移过程中起关键作用。近年来,探索克服MDSCs的免疫抑制,从而增强抗肿瘤治疗疗效的研究已经成为研究热点。在这篇综述中,我们讨论了靶向MDSCs以及与ICI联合治疗的进展,并总结了MDSCs对肺癌患者预后的影响。     

S-1 eliminates MDSCs and enhances the efficacy of PD-1 blockade via regulation of tumor-derived Bv8 and S100A8 in thoracic tumor

Myeloid-derived suppressor cells (MDSCs) have been known to play a pivotal role in the induction of immune tolerance, which limits the benefits of immune checkpoint inhibitors (ICIs). Recent studies revealed that several chemotherapeutic agents decreased tumor-infiltrating MDSCs. Therefore, combination therapy with cytotoxic chemotherapeutic agents and ICIs was approved for first-line treatment for lung cancer. However, the impact of chemotherapeutic agents on MDSCs and an optimal partner of ICIs has not been fully investigated in thoracic tumors, including lung cancer and malignant pleural mesothelioma. In the present study, we found that treatment with 5-FU and its oral formulation, S-1, suppressed tumor progression and inhibited the accumulation of MDSCs in thoracic tumor-bearing mice. Tumor-infiltrating T cells and dendritic cells were significantly expanded in S-1-treated mice. 5-FU suppressed the ability of tumor cells to recruit MDSCs, while it did not suppress the survival and differentiation of mouse MDSCs in vitro. We also revealed that 5-FU or S-1 significantly downregulated the expression of tumor-derived Bv8 and S100A8. The knockdown of Bv8 or S100A8 in tumor cells suppressed tumor growth and MDSC recruitment in vivo. Furthermore, in comparison with pemetrexed, administration of S-1 improved the synergistic therapeutic efficacy of anti-PD-1 antibodies with or without carboplatin. Our findings revealed a novel mechanism wherein S-1 primed a favorable tumor microenvironment to provide the rationale for combination therapy with S-1 and ICIs as the optimal therapy for thoracic cancer.     

髓源性抑制细胞在肿瘤发生发展中的作用

髓源性抑制细胞(myeloid-derived suppressor cells,MDSCs)是一组异质细胞,在肿瘤相关免疫抑制中起关键作用.MDSCs通过免疫抑制作用,使肿瘤逃避免疫监控.肿瘤组织中MDSCs的浸润与患者预后不良及治疗的抵抗密切相关.MDSCs在转移中发挥重要作用,但MDSCs在远处器官建立转移前微环...     

髓源抑制性细胞的功能及其逆转策略

髓源抑制性细胞（myeloid-derived suppressor cell,MDSC）是在骨髓中产生的一群具有高度异质性的免疫抑制细胞, 在 肿瘤等病理状态下大量聚集,是促进肿瘤进展、降低患者对传统治疗反应性的关键因素。近年来,免疫检查点阻断剂和基因工程 T细胞过继回输治疗延长了许多晚期恶性肿瘤患者的生存期,但上述免疫疗法在肺癌、结直肠癌等实体瘤中有效率仅为 15%~40%,这与实体瘤免疫抑制微环境密切相关。MDSC在肿瘤微环境中聚集,通过抑制T细胞或NK细胞增殖及功能减弱宿主 抗肿瘤免疫反应,是患者对免疫治疗耐受的关键机制。因此,明确MDSC聚集及功能特征是探索提高免疫治疗效果的重要研究 方向。本文将系统阐述MDSC的产生、聚集及其免疫抑制功能的调控机制,概述目前靶向MDSC治疗的最新研究进展。     

Improving radioresponse through modification of the tumor immunological microenvironment

Radioresponse is influenced by factors apart from the targeted cancer cells; in fact, endothelial cells and infiltrating immune cells within the tumor microenvironment (TME) are the two main components affecting the outcome of radiotherapy. The benefits of fractionated radiotherapy are attenuated through the upregulation of hypoxia inducible factor-1 α and vascular endothelial growth factor. The therapeutic effect of antiangiogenic agents is counteracted by the mobilization of endogenous proangiogenic cells to the TME. This study highlights the importance of radiation timing within a vascular normalization window and discusses the importance of immune cells that comprise the microenvironment. A balance between favorable tumor-infiltrating immune cells, including cytotoxic T cells, natural killer cells, and dendritic cells, and the unfavorable cells, such as tumor-associated macrophages and regulatory T cells, determines the final tumor-control probability. The reciprocal complementation between combinations of radiotherapy and immunotherapy strategies through modulation of the tumor immunological microenvironment may yield promising results in the future.     

髓源性抑制细胞和调节性T细胞在感染和肿瘤微环境中的免疫抑制机制

髓源性抑制细胞(MDSC)和调节性T细胞(Treg)是重要的抑制性免疫细胞,在炎症、感染和肿瘤中大量扩增,可通过多种机制抑制机体抗肿瘤免疫,促进肿瘤生长和转移.寻找肿瘤微环境中MDSC、Treg细胞升高的原因及清除方法,已成为肿瘤免疫治疗的研究热点.     

肿瘤微环境中免疫与炎症的调节

免疫和炎症构成肿瘤微环境的两大核心,但两者之间关系并不清楚。髓源抑制性细胞(myeloid derived suppressorcell,MDSC)和调节性T细胞(regulatory T cell,Treg)等抑制性细胞趋化至肿瘤部位可抑制炎症,而非介导肿瘤免疫逃逸;肥大细胞则通过对MDSC和Treg的调节,介导免疫和炎症的对话;作为肿瘤微环境中基本信号通路的Toll样信号可以直接调节免疫和炎症,并通过微颗粒途径精细调控肿瘤炎症的稳定。不管肿瘤炎症和免疫的关系如何复杂而交错,一般认为,肿瘤微环境的抗肿瘤免疫和炎症呈现出一种负相关关系,即在肿瘤的早期,免疫反应较强而炎症较弱;但在肿瘤的后期,免疫反应较弱而炎症较强。     

心理应激对肿瘤微环境中免疫细胞影响的研究进展

肿瘤微环境(Tumor microenvironment,TME)在肿瘤的发生发展中发挥重要作用。应激状态下的人体通常会经历一些重要的生物效应,从而损害免疫系统,各种应激反应可以通过调节肿瘤微环境中的免疫细胞,例如自然杀伤细胞、树突状细胞、髓系来源抑制细胞(MDSCs)等,导致肿瘤进展。由于免疫细胞对人体的多项活动都起着重要的调节作用,并且其在肿瘤中的应用也具有十分重要的意义。本文就心理应激如何影响肿瘤微环境中的免疫细胞做一综述,旨在为肿瘤治疗提供新的思路。     

Targeting myeloid-derived suppressor cells for cancer therapy

The emergence and clinical application of immunotherapy is considered a promising breakthrough in cancer treatment. According to the literature, immune checkpoint blockade (ICB) has achieved positive clinical responses in different cancer types, although its clinical efficacy remains limited in some patients. The main obstacle to inducing effective antitumor immune responses with ICB is the development of an immunosuppressive tumor microenvironment. Myeloid-derived suppressor cells (MDSCs), as major immune cells that mediate tumor immunosuppression, are intimately involved in regulating the resistance of cancer patients to ICB therapy and to clinical cancer staging and prognosis. Therefore, a combined treatment strategy using MDSC inhibitors and ICB has been proposed and continually improved. This article discusses the immunosuppressive mechanism, clinical significance, and visualization methods of MDSCs. More importantly, it describes current research progress on compounds targeting MDSCs to enhance the antitumor efficacy of ICB.     

The cancer stem cell niche: cross talk between cancer stem cells and their microenvironment

Despite recent progresses in tumor therapy and increased knowledge in tumor biology, tumor remains a common and lethal disease worldwide. Cancer stem cells (CSCs) are a subset of cancer cells with a stem cell-like ability, which may drive tumor growth and recurrence and are resistant to many current anticancer treatments. Solid tumors are regarded as “organs” which are comprised of cancer cells and the tumor stroma. The tumor microenvironment makes up the stroma of the tumor, which occupies the majority of the tumor mass, including the extracellular matrix (ECM), mesenchymal stem cells (MSCs), endothelial cells, immune cells, and, what is more, networks of cytokines and growth factors. The microenvironment or niche surrounding CSCs largely governs their cellular fate. Recent work has revealed that the microenvironment supports CSC self-renewal and simultaneously serves as a physical barrier to drug delivery. The tumor microenvironment plays pivotal roles in each stage of tumor development. Knowledge about the interactions of CSCs with their microenvironment would seem to be of most importance for developing new treatment strategies.     

Tumor microenvironment in gastric cancers

The tumor microenvironment favors the growth and expansion of cancer cells. Many cell types are involved in the tumor microenvironment such as inflammatory cells, fibroblasts, nerves, and vascular endothelial cells. These stromal cells contribute to tumor growth by releasing various molecules to either directly activate the growth signaling in cancer cells or remodel surrounding areas. This review introduces recent advances in findings on the interactions within the tumor microenvironment such as in cancer‐associated fibroblasts (CAFs), immune cells, and endothelial cells, in particular those established in mouse gastric cancer models. In mice, myofibroblasts in the gastric stroma secrete R‐spondin and support normal gastric stem cells. Most CAFs promote tumor growth in a paracrine manner, but CAF population appears to be heterogeneous in terms of their function and origin, and include both tumor‐promoting and tumor‐restraining populations. Among immune cell populations, tumor‐associated macrophages, including M1 and M2 macrophages, and myeloid‐derived suppressor cells (MDSCs), are reported to directly or indirectly promote gastric tumorigenesis by secreting soluble factors or modulating immune responses. Endothelial cells or blood vessels not only fuel tumors with nutrients, but also interact with cancer stem cells and immune cells by secreting chemokines or cytokines, and act as a cancer niche. Understanding these interactions within the tumor microenvironment would contribute to unraveling new therapeutic targets.     

Interleukin-10 ablation promotes tumor development, growth, and metastasis

Interleukin-10 (IL-10) is a broadly acting immune inhibitory cytokine that is generally thought to support tumor growth. Here we challenge this view with evidence that genetic ablation of IL-10 in the mouse significantly heightens sensitivity to chemical carcinogenesis, growth of transplanted tumors, and formation of metastases. Tumor growth in IL-10-deficient (IL-10(-/-)) mice was associated with an increased level of myeloid-derived suppressor cells (MDSC) and CD4(+)Foxp3(+) regulatory T (Treg) cells in both the tumor microenvironment and the tumor-draining lymph nodes. IL-10(-/-) MDSCs express high levels of MHC and IL-1, and they efficiently induced formation of Treg cells. IL-1 signaling blockade reduced tumor growth mediated by IL-10 deficiency, associated with a partial rescue of tumor infiltration and function of effector T cells and a decrease in tumor angiogenesis and tumor infiltration by Treg cells. Taken together, our findings establish that endogenous IL-10 inhibits inflammatory cytokine production and hampers the development of Treg cells and MDSCs, two key components of the immunosuppressive tumor microenvironment, thereby inhibiting tumor development, growth, and metastasis.     

The immunobiology of myeloid-derived suppressor cells in cancer

The tumor microenvironment is a complex and heterogeneous milieu in which multiple interactions occur between tumor and host cells. Immunosuppressive cells which are present in this microenvironment, such as regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs), play an important role in tumor progression, via down-regulation of antitumor responses. MDSCs represent a heterogeneous group of cells originated from the myeloid lineage that are in the immature state. These cells markedly accumulate under pathologic conditions, such as cancer, infection, and inflammation, and use various mechanisms to inhibit both adaptive and innate immune responses. These immunosuppressive mechanisms include deprivation of T cells from essential amino acids, induction of oxidative stress, interference with viability and trafficking of T cells, induction of immunosuppressive cells, and finally polarizing immunity toward a tumor-promoting type 2 phenotype. In addition to suppression of antitumor immune responses, MDSCs can also enhance the tumor metastasis and angiogenesis. Previous studies have shown that increased frequency of MDSCs is related to the tumor progression. Moreover, various drugs that directly target these cells or reverse their suppressive activity can improve antitumor immune responses as well as increase the efficacy of immunotherapeutic intervention. In this review, we will first discuss on the immunobiology of MDSCs in an attempt to find the role of these cells in tumor progression and then discuss about therapeutic approaches to target these cells.     

Novel therapies for metastatic castrate-resistant prostate cancer

Recent advances in tumor biology have made remarkable achievements in the development of therapy for metastatic castrate-resistant prostate cancer. These advances reflect a growing appreciation for the role of the tumor microenvironment in promoting prostate cancer progression. Prostate cancer is no longer viewed predominantly as a disease of abnormally proliferating epithelial cells but rather as a disease of complex interactions between prostate cancer epithelial cells (epithelial compartment) and the surrounding tissues (stromal compartment) in which they reside. For example, prostate cancers frequently metastasize to bone, an organ that contains a microenvironment rich in extracellular matrix proteins and stromal cells including hematopoietic cells, osteoblasts, osteoclasts fibroblasts, endothelial cells, adipocytes, immune cells, and mesenchymal stem cells. Multiple signaling pathways provide crosstalk between the epithelial and the stromal compartments to enhance tumor growth, including androgen receptor signaling, tyrosine kinase receptor signaling, and immune surveillance. The rationale to disrupt this "two-compartment" crosstalk has led to the development of drugs that target tumor stromal elements in addition to the cancer epithelial cell.     

Curcumin induces the differentiation of myeloid-derived suppressor cells and inhibits their interaction with cancer cells and related tumor growth

Myeloid-derived suppressor cells (MDSC) accumulate in the spleen and tumors and contribute to tumor growth, angiogenesis, and progression. In this study, we examined the effects of curcumin on the activation and differentiation of MDSCs, their interaction with human cancer cells, and related tumor growth. Treatment with curcumin in the diet or by intraperitoneal injection significantly inhibited tumorigenicity and tumor growth, decreased the percentages of MDSCs in the spleen, blood, and tumor tissues, reduced interleukin (IL)-6 levels in the serum and tumor tissues in a human gastric cancer xenograft model and a mouse colon cancer allograft model. Curcumin treatment significantly inhibited cell proliferation and colony formation of cancer cells and decreased the secretion of murine IL-6 by MDSCs in a coculture system. Curcumin treatment inhibited the expansion of MDSCs, the activation of Stat3 and NF-κB in MDSCs, and the secretion of IL-6 by MDSCs, when MDSCs were cultured in the presence of IL-1β, or with cancer cell- or myofibroblast-conditioned medium. Furthermore, curcumin treatment polarized MDSCs toward a M1-like phenotype with an increased expression of CCR7 and decreased expression of dectin 1 in vivo and in vitro. Our results show that curcumin inhibits the accumulation of MDSCs and their interaction with cancer cells and induces the differentiation of MDSCs. The induction of MDSC differentiation and inhibition of the interaction of MDSCs with cancer cells are potential strategies for cancer prevention and therapy.     

Extracellular vesicle long non–coding RNA‐mediated crosstalk in the tumor microenvironment: Tiny molecules,huge roles

Emerging evidence has shown that dynamic crosstalk among cells in the tumor microenvironment modulates the progression and chemotherapeutic responses of cancer. Extracellular vesicles comprise a crucial form of intracellular communication through horizontal transfer of bioactive molecules, including long non–coding RNA (lncRNA), to neighboring cells. Three main types of extracellular vesicles are exosomes, microvesicles and apoptotic bodies, exhibiting a wide range of sizes and different biogenesis. Over the last decade, dysregulation of extracellular vesicle lncRNA has been revealed to remodel the tumor microenvironment and induce aggressive phenotypes of tumor cells, thereby facilitating tumor growth and development. This review will focus on extracellular vesicle lncRNA‐mediated crosstalk between tumor cells and recipient cells, including tumor cells as well as stromal cells in the tumor microenvironment, and overview the mechanisms by which lncRNA are selectively sorted into extracellular vesicles, which may pave the way for their clinical application in cancer diagnosis and treatment.     

MicroRNA‐155 deficiency enhances the recruitment and functions of myeloid‐derived suppressor cells in tumor microenvironment and promotes solid tumor growth

Immune cells in tumor microenvironment play a prominent role in tumor progression and metastasis. MicroRNA‐155 (miR‐155) represents an important player in innate and adaptive immunity by regulating differentiation, maturation and activation of macrophages, dendritic cells, B cells and T cells. However, the role of miR‐155 expression in immune cells in solid tumor development is less elucidated. Our current study showed that both B16‐F10 melanoma and Lewis lung carcinoma tumors grew much faster in bic/miR‐155 knockout (miR‐155^?/?) mice along with an increase of myeloid‐derived suppressor cells (MDSCs) accumulation in tumors, compared to that in wild‐type mice. Bone marrow transplantation study showed that bone marrow miR‐155 deficiency could replicate the above tumor‐promoting phenotype. In vitro study demonstrated that tumor‐infiltrating miR‐155^?/? MDSCs showed greater migration ability and expressed higher level of multiple chemokines. Furthermore, we found that the level of HIF‐1α, a direct target of miR‐155, was increased in miR‐155 deficient MDSCs, and that the increased HIF‐1α upregulated CXCL1, CXCL3 and CXCL8 expression in MDSCs, contributing to the enhanced recruitment of miR‐155^?/? MDSCs to the tumors. Moreover, miR‐155^?/? MDSCs showed enhanced immunosuppressive and pro‐angiogenic capacities. Taken together, our study, for the first time, demonstrated that miR‐155 deficiency promoted solid tumor growth through increasing the recruitment of MDSCs to tumor microenvironment and enhancing the tumor‐promoting functions of the recruited MDSCs. Thus, upregulating miR‐155 expression in MDSCs may be developed as a therapeutic approach to halt tumor development.     

Chemokines and the microenvironment in neuroectodermal tumor–host interaction

Chemokines and chemokine receptors play an important role in immune homeostasis and surveillance. Altered or defective expression of chemokines and/or chemokine receptors could lead to a disease state including autoimmune disorder or cancer. Tumors from glioblastoma, melanoma, and neuroblastoma secrete high levels of chemokines that can promote tumor growth and progression or induce stromal cells present in the tumor microenvironment to produce cytokines or chemokines which, in turn, can regulate angiogenesis, tumor growth, and metastasis. On the other hand, chemokines secreted by tumor or stromal cells can also attract leukocytes such as dendritic cells, macrophages, neutrophils, and lymphocytes which may downmodulate tumor growth. New therapies that are aimed at limiting tumor growth and progression by attracting immune effector cells to the tumor site with chemokines may hold the key to the successful treatment of cancer, although this approach may be hampered by possible tumor growth-stimulating effects of chemokines.     

The tumor microenvironment in hepatocellular carcinoma: current status and therapeutic targets

A growing body of literature highlights the cross-talk between tumor cells and the surrounding peri-tumoral stroma as a key modulator of the processes of hepatocarcinogenesis, epithelial mesenchymal transition (EMT), tumor invasion and metastasis. The tumor microenvironment can be broadly classified into cellular and non-cellular components. The major cellular components include hepatic stellate cells, fibroblasts, immune, and endothelial cells. These cell types produce the non-cellular components of the tumor stroma, including extracellular matrix (ECM) proteins, proteolytic enzymes, growth factors and inflammatory cytokines. The non-cellular component of the tumor stroma modulates hepatocellular carcinoma (HCC) biology by effects on cancer signaling pathways in tumor cells and on tumor invasion and metastasis. Global gene expression profiling of HCC has revealed that the tumor microenvironment is an important component in the biologic and prognostic classification of HCC. There are substantial efforts underway to develop novel drugs targeting tumor-stromal interactions. In this review, we discuss the current knowledge about the role of the tumor microenvironment in pathogenesis of HCC, the role of the tumor microenvironment in the classification of HCC and efforts to develop treatments targeting the tumor microenvironment.