Paclitaxel promotes differentiation of myeloid-derived suppressor cells into dendritic cells in vitro in a TLR4-independent manner

Myeloid cells play a key role in the outcome of anti-tumor immunity and response to anti-cancer therapy, since in the tumor microenvironment they may exert both stimulatory and inhibitory pressures on the proliferative, angiogenic, metastatic, and immunomodulating potential of tumor cells. Therefore, understanding the mechanisms of myeloid regulatory cell differentiation is critical for developing strategies for the therapeutic reversal of myeloid derived suppressor cell (MDSC) accumulation in the tumor-bearing hosts. Here, using an in vitro model system, several potential mechanisms of the direct effect of paclitaxel on MDSC were tested, which might be responsible for the anti-tumor potential of low-dose paclitaxel therapy in mice. It was hypothesized that a decreased level of MDSC in vivo after paclitaxel administration might be due to (i) the blockage of MDSC generation, (ii) an induction of MDSC apoptosis, or (iii) the stimulation of MDSC differentiation. The results revealed that paclitaxel in ultra-low concentrations neither increased MDSC apoptosis nor blocked MDSC generation, but stimulated MDSC differentiation towards dendritic cells. This effect of paclitaxel was TLR4-independent since it was not diminished in cell cultures originated from TLR4^?/? mice. These results support a new concept that certain chemotherapeutic agents in ultra-low non-cytotoxic doses may suppress tumor progression by targeting several cell populations in the tumor microenvironment, including MDSC.     

Application of paclitaxel in low non-cytotoxic doses supports vaccination with melanoma antigens in normal mice

Chemotherapeutic agents such as paclitaxel applied in ultra-low, non-cytotoxic doses were previously shown to stimulate dendritic cell activity and anti-tumor immune responses upon vaccination in mouse transplantable tumor models. However, the mechanisms of these alterations-termed chemoimmunomodulation or chemomodulation-are still not clear. This study investigated the effect of paclitaxel applied in ultra-low, non-cytotoxic doses on the efficiency of immunization of healthy C57BL/6 mice with the peptide derived from tyrosinase related protein (TRP)-2 as a model melanoma antigen. Using an IFNγ ELISPOT assay, it was found that administration of 1 mg paclitaxel/kg in combination with the peptide vaccination strongly increased the frequencies of TRP-2 specific spleen T-cells as compared to levels due to the vaccination alone. This was associated with a significant decrease in the levels of regulatory T-cells (T_reg) and immature myeloid cells (known as a counterpart of myeloid derived suppressor cells [MDSC] in healthy mice). Such impairments of potential immunosuppressive cells were found to correlate with a strong increase in the amount of effector CD8⁺ and CD4⁺ T-cells in the bone marrow and spleen. Furthermore, in paclitaxel-treated mice, a significant augmentation of natural killer (NK) cell numbers in the bone marrow and their ability to produce IFNγ were observed. In addition, the level of NK-T-cells in the lymph nodes was also increased. It is suggested that paclitaxel applied in ultra-low, non-cytotoxic doses may potentially enhance the efficacy of anti-tumor vaccinations by neutralizing immunosuppressive T_reg and MDSC populations in tumor-bearing hosts.     

Application of paclitaxel in low non-cytotoxic doses supports vaccination with melanoma antigens in normal mice

Chemotherapeutic agents such as paclitaxel applied in ultra-low, non-cytotoxic doses were previously shown to stimulate dendritic cell activity and anti-tumor immune responses upon vaccination in mouse transplantable tumor models. However, the mechanisms of these alterations-termed chemoimmunomodulation or chemomodulation-are still not clear. This study investigated the effect of paclitaxel applied in ultra-low, non-cytotoxic doses on the efficiency of immunization of healthy C57BL/6 mice with the peptide derived from tyrosinase related protein (TRP)-2 as a model melanoma antigen. Using an IFNγ ELISPOT assay, it was found that administration of 1 mg paclitaxel/kg in combination with the peptide vaccination strongly increased the frequencies of TRP-2 specific spleen T-cells as compared to levels due to the vaccination alone. This was associated with a significant decrease in the levels of regulatory T-cells (T(reg)) and immature myeloid cells (known as a counterpart of myeloid derived suppressor cells [MDSC] in healthy mice). Such impairments of potential immunosuppressive cells were found to correlate with a strong increase in the amount of effector CD8+ and CD4+ T-cells in the bone marrow and spleen. Furthermore, in paclitaxel-treated mice, a significant augmentation of natural killer (NK) cell numbers in the bone marrow and their ability to produce IFNγ were observed. In addition, the level of NK-T-cells in the lymph nodes was also increased. It is suggested that paclitaxel applied in ultra-low, non-cytotoxic doses may potentially enhance the efficacy of anti-tumor vaccinations by neutralizing immunosuppressive T(reg) and MDSC populations in tumor-bearing hosts.     

Systemic injection of TLR1/2 agonist improves adoptive antigen-specific T cell therapy in glioma-bearing mice

Adoptive immunotherapy is an attractive strategy for glioma treatment. However, some obstacles still need be overcome. In this study, GL261-bearing mice treated with adoptively transferred antigen-specific T cells and systemic injection of bacterial lipoprotein (BLP), a TLR1/2 agonist, got a long-term survival and even immune protection. By analyzing adoptive T cells, it was found that BLP maintained T cell survival, proliferation and anti-tumor efficacy in the brains of tumor-bearing hosts. Moreover, tumor microenvironment was modified by up-regulating IFN-γ-secreting CD8+ T cells and down-regulating MDSC, which might be related with high CXCL10 and low CCL2 expression. In addition, TLR2 deficiency abrogated therapeutic effect with increased MDSC accumulation and decreased IFN-γ-secreting CD8+ T cells in the brains. Thus, the systemic injection of BLP could improve the adoptive T cell therapy by maintaining T cell persistence, modifying the tumor microenvironment and even inducing systemic anti-tumor immunity, which might offer a clinically promising immunotherapeutic strategy for glioma.     

Myeloid derived suppressor cells in tumor microenvironment: Interaction with innate lymphoid cells

Human myeloid-derived suppressor cells (MDSC) represent a stage of immature myeloid cells and two main subsets can be identified: monocytic and polymorphonuclear. MDSC contribute to the establishment of an immunosuppressive tumor microenvironment (TME). The presence and the activity of MDSC in patients with different tumors correlate with poor prognosis. As previously reported, MDSC promote tumor growth and use different mechanisms to suppress the immune cell-mediated anti-tumor activity. Immunosuppression mechanisms used by MDSC are broad and depend on their differentiation stage and on the pathological context. It is known that some effector cells of the immune system can play an important role in the control of tumor progression and metastatic spread. In particular, innate lymphoid cells (ILC) contribute to control tumor growth representing a potential, versatile and, immunotherapeutic tool. Despite promising results obtained by using new cellular immunotherapeutic approaches, a relevant proportion of patients do not benefit from these therapies. Novel strategies have been investigated to overcome the detrimental effect exerted by the immunosuppressive component of TME (i.e. MDSC). In this review, we summarized the characteristics and the interactions occurring between MDSC and ILC in different tumors discussing how a deeper knowledge on MDSC biology could represent an important target for tumor immunotherapy capable of decreasing immunosuppression and enhancing anti-tumor activity exerted by immune cells.     

Myeloid‐derived suppressor cells in inflammation: Uncovering cell subsets with enhanced immunosuppressive functions

Although originally described in tumor‐bearing hosts, myeloid‐derived suppressor cells (MDSC) have been detected under numerous pathological situations that cause enhanced demand of myeloid cells. Thus, MDSC might be part of a conserved response to different endogenous and exogenous stress signals, including inflammation. Two processes are fundamental for MDSC biology: differentiation from myeloid progenitors and full activation of their immune regulatory program by factors released from activated T cells or present in the microenvironment conditioned by either tumor growth or inflammation. How these two processes are controlled and linked is still an open question. In this issue of the European Journal of Immunology, a paper demonstrates that a combination of the known inflammatory molecules, IFN‐γ and LPS, sustains MDSC expansion and activation while suppressing differentiation of DC from bone marrow precursors. Moreover, this paper contributes to defining the cell subsets that possess immunoregulatory properties within the broad population of CD11b⁺Gr‐1⁺ cells, often altogether referred to as MDSC.     

髓系来源抑制细胞促进肿瘤免疫逃逸的研究进展

髓系来源抑制细胞(MDSC)是髓系来源的一群异质细胞,在荷瘤小鼠模型及肿瘤患者均发挥免疫抑制作用.肿瘤MDSC免疫逃逸作用的机制目前已取得了很多进展,这群细胞可以通过上调精氨酸酶1(ARN1),诱导一氧化氮合酶(iNOS or NOS-2)表达,增加一氧化氮(NO)、活化氧自由基(ROS)等的释放,分解肿瘤微环境中的半...     

Complement activation in cancer: Effects on tumor-associated myeloid cells and immunosuppression

Cancer-related inflammation plays a central role in the establishment of tumor-promoting mechanisms. Tumor-associated myeloid cells, which engage in complex interactions with cancer cells, as well as stromal and tumor immune infiltrating cells, promote cancer cell proliferation and survival, angiogenesis, and the generation of an immunosuppressive microenvironment. The complement system is one of the inflammatory mechanisms activated in the tumor microenvironment. Beside exerting anti-tumor mechanisms such as complement-dependent cytotoxicity and phagocytosis induced by therapeutic monoclonal antibodies, the complement system may promote immunosuppression and tumor growth and invasiveness, in particular, through the anaphylatoxins which target both leukocytes and cancer cells. In this review, we will discuss complement-mediated mechanisms acting on leukocytes, in particular on cells of the myelomonocytic cell lineage (macrophages, neutrophils, myeloid derived suppressor cells), which promote myeloid cell recruitment and functional skewing, leading to immunosuppression and resistance to tumor-specific immunity. Pre-clinical studies, which have elucidated the role of complement in activating pro-tumor mechanisms in myeloid cells, showing the relevance of these mechanisms in human, and therapeutic approaches based on complement targeting support the hypothesis that complement directly and indirectly interferes with many of the effector pathways associated with the cancer–immunity cycle, suggesting the relevance of complement targeting to improve responses to immunotherapeutic approaches.     

IL-1β regulates a novel myeloid-derived suppressor cell subset that impairs NK cell development and function

Chronic inflammation is associated with promotion of malignancy and tumor progression. Many tumors enhance the accumulation of myeloid-derived suppressor cells (MDSC), which contribute to tumor progression and growth by suppressing anti-tumor immune responses. Tumor-derived IL-1β secreted into the tumor microenvironment has been shown to induce the accumulation of MDSC possessing an enhanced capacity to suppress T cells. In this study, we found that the enhanced suppressive potential of IL-1β-induced MDSC was due to the activity of a novel subset of MDSC lacking Ly6C expression. This subset was present at low frequency in tumor-bearing mice in the absence of IL-1β-induced inflammation; however, under inflammatory conditions, Ly6C(neg) MDSC were predominant. Ly6C(neg) MDSC impaired NK cell development and functions in vitro and in vivo. These results identify a novel IL-1β-induced subset of MDSC with unique functional properties. Ly6C(neg) MDSC mediating NK cell suppression may thus represent useful targets for therapeutic interventions.     

Myeloid-derived suppressor cells: the dark knight or the joker in viral infections?

Myeloid derived suppressor cells (MDSCs) are immature cells of myeloid origin, frequently found in tumor microenvironments and in the blood of cancer patients. In recent years, MDSCs have also been found in non-cancer settings, including a number of viral infections. The evasion of host immunity employed by viruses to establish viral persistence strikingly parallels mechanisms of tumor escape, prompting investigations into the generation and function of MDSCs in chronic viral infections. Importantly, analogous to the tumor microenvironment, MDSCs effectively suppress antiviral host immunity by limiting the function of several immune cells including T cells, natural killer cells, and antigen-presenting cells. In this article, we review studies on the mechanisms of MDSC generation, accumulation, and survival in an effort to understand their emergent importance in viral infections. We include a growing list of viral infections in which MDSCs have been reported. Finally, we discuss how MDSCs might play a role in establishing chronic viral infections and identify potential therapeutics that target MDSCs.     

Kinase inhibitor Sorafenib modulates immunosuppressive cell populations in a murine liver cancer model

Accumulating evidence suggests that regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC) are elevated in cancer patients and tumor-bearing hosts, and that depletion of Tregs and MDSC may enhance the anti-tumor immunity of the host. Sorafenib, a novel multi-kinase inhibitor, is approved for the treatment of several human cancers, including advanced hepatocellular carcinoma (HCC). Sorafenib is believed to inhibit tumor growth via anti-angiogenesis, cell cycle arrest, and inducing apoptosis. However, the impact of Sorafenib on immune cell populations in tumor-bearing hosts is unclear. In this report, we show that Tregs and MDSC are increased in the spleens and bone marrows of the BALB/c mice with liver hepatoma. The increase in Tregs and MDSC was positively correlated with tumor burden. Treatment of Sorafenib not only inhibited HCC cell growth in mice but also significantly decreased the suppressive immune cell populations: Tregs and MDSC. In conclusion, our study strongly suggests that Sorafenib can enhance anti-tumor immunity via modulating immunosuppressive cell populations in the murine liver cancer model.     

髓系抑制细胞抑制机体抗肿瘤免疫机制及相关免疫治疗的研究进展

髓系抑制细胞为未成熟的髓系细胞,在肿瘤组织中大量聚集。髓系抑制细胞可通过多种机制抑带0细胞毒性T细胞和自然杀伤细胞。自然杀伤T细胞对肿瘤的杀伤或通过诱导调节性T细胞（Treg）抑制机体抗肿瘤免疫从而促进肿瘤进展,因而抑制髓系抑制细胞将成为肿瘤免疫治疗的新靶点。     

Antigen specificity of immune suppression by myeloid-derived suppressor cells

Among the mechanisms set in motion by the tumor to escape the control of the immune system, MDSCs play a central role in inducing tolerance to a variety of anti-tumor effectors, including T lymphocytes. It has been demonstrated that MDSCs expand in tumor-bearing mice and in cancer patients, leading to an impairment of T cell reactivity against the tumor. However, as the presence of MDSCs is not correlated with a general immune suppression, it was advanced that a mechanism regulating the specificity of MDSC inhibition must be present. In this article, we review the literature showing that MDSCs exert their immune-suppressive function on Ag-specific T cell responses but at times, also on mitogen-activated T lymphocytes, therefore bypassing the Ag dependency. We propose that the features of MDSC-mediated immune suppression might be influenced not only by the specific microenvironment in which MDSCs expand and by the tumor characteristics but also by the levels of activation of the target lymphocytes.     

髓样抑制细胞免疫抑制机理的研究

目的:研究荷瘤小鼠来源的髓样抑制细胞(Myeloid derived suppressor cell,MDSC)在肿瘤免疫抑制中的作用机理。方法:用Percoll分离法从荷瘤小鼠的脾脏和骨髓中分离Gr-1+CD11b+MDSC;用流式细胞术检测MDSC对T细胞增殖的抑制作用;分别用生化法和ELISA技术检测MDSC体外培养上清中抑制性因子NO、ROS和IL-10、TGF-β的含量。结果:MDSC在荷瘤小鼠的脾脏和骨髓中聚集增多,且其在骨髓中所占的比例显著高于脾脏;MDSC可以明显抑制脾脏细胞的增殖,体外培养6小时的MDSC可以分泌大量NO、ROS和IL-10、TGF-β。结论:本实验进一步证实MDSC可以通过分泌大量NO、ROS和IL-10、TGF-β抑制T细胞增殖。     

小鼠肺肿瘤发展过程中外周血NKT和MDSC细胞变化

目的：探讨小鼠肺癌细胞生长过程中自然杀伤性T细胞（NKT）和骨髓源性抑制细胞（MDSC）变化。方法：采用小鼠Lewis肺癌细胞系（LLC）制备小鼠皮下肿瘤模型,在肿瘤生长不同时间取鼠尾血,提取白细胞进行相关抗体染色,采用流式细胞仪进行NKT和MDSC细胞检测。结果：肺癌小鼠随着肿瘤增大外周血NKT细胞比例逐渐降低,而MDSC细胞比例逐渐增加,与正常对照小鼠相比,二者均存在显著差异。结论：小鼠NKT细胞和MDSC细胞在肺肿瘤发展过程中呈相反趋势变化,二者可作为肺癌发展的潜在监测指标。     

Mechanisms of tumor escape: role of tumor microenvironment in inducing apoptosis of cytolytic effector cells

Spontaneous tumors grow and kill the host unless therapy reduces their mass to a level where the immune system, it is thought, can control their growth and diffusion. Indeed, in many instances tumors can reappear, become resistant to therapy, and escape the host immune response. Many mechanisms of tumor escape operating in the tumor microenvironment have been proposed: 1) low or absent expression of molecules on tumor cells involved in tumor target cell recognition; 2) absence of co-stimulation leading to tolerization of T cells; 3) soluble factors secreted by tumor cells inhibiting T cell response; and 4) regulatory T cells, myeloid suppressor cells, and stromal cells may impair immune-cell responses to tumors. Furthermore, tumors can release soluble molecules such as HLA-I (sHLA-I). This, in turn, reduces T cell-mediated immune response and induces apoptosis of cytolytic effector cells such as natural killer and CD8⁺ T lymphocytes through the engagement of HLA-I receptors such as CD8 and/or activating isoforms of the inhibitory receptor superfamily. The release of soluble ligand for activating receptors, e.g. UL16 binding proteins and/or MHC class I-related proteins A and B, the natural ligands of NKG2D, may impair activation, effector cell-mediated recognition, and cytolysis of tumor cells. Furthermore, the elimination of anti-tumor effector cells may be achieved by induction of apoptosis consequent to triggering elicited via activating molecules, such as receptors responsible for natural cytotoxicity, upon their binding with ligands expressed on tumor cells.     

Notch1 signalling controls the differentiation and function of myeloid-derived suppressor cells in systemic lupus erythematosus

Emerging studies have reported the expansion of myeloid-derived suppressor cells (MDSCs) in some autoimmune disorders, such as systemic lupus erythematosus (SLE), but the detailed molecular mechanisms of the aberrant expansion in SLE are still unclear. In the present study, we confirmed that the increased MDSCs positively correlated with disease activity in SLE patients. The suppressive capacity of MDSCs from patients with high activity was lower than that of MDSCs from patients with low activity. Moreover, the potential precursors for MDSCs, common myeloid progenitors (CMPs) and granulocyte–monocyte progenitors (GMPs), were markedly increased in the bone marrow (BM) aspirates of SLE patients. As an important regulator of cell fate decisions, aberrant activation of Notch signalling was reported to participate in the pathogenesis of SLE. We found that the expression of Notch1 and its downstream target gene hairy and enhancer of split 1 (Hes-1) increased markedly in GMPs from SLE patients. Moreover, the Notch1 signalling inhibitor DAPT profoundly relieved disease progression and decreased the proportion of MDSCs in pristane-induced lupus mice. The frequency of GMPs was also decreased significantly in lupus mice after DAPT treatment. Furthermore, the inhibition of Notch1 signalling could limit the differentiation of MDSCs in vitro. The therapeutic effect of DAPT was also verified in Toll-like receptor 7 (TLR7) agonist-induced lupus mice. Taken together, our results demonstrated that Notch1 signalling played a crucial role in MDSC differentiation in SLE. These findings will provide a promising therapy for the treatment of SLE.     

Role of myeloid-derived suppressor cells in autoimmune disease

Myeloid-derived suppressor cells(MDSCs) represent an important class of immunoregulatory cells that can be activated to suppress T cell functions. These MDSCs can inhibit T cell functions through cell surface interactions and the release of soluble mediators. MDSCs accumulate in the inflamed tissues and lymphoid organs of patients with autoimmune diseases. Much of our knowledge of MDSC function has come from studies involving cancer models, however many recent studies have helped to characterize MDSC involvement in autoimmune diseases. MDSCs are a heterogeneous group of immature myeloid cells with a number of different functions for the suppression of T cell responses. However, we have yet to fully understand their contributions to the development and regulation of autoimmune diseases. A number of studies have described beneficial functions of MDSCs during autoimmune diseases, and thus there appears to be a potential role for MDSCs in the treatment of these diseases. Nevertheless, many questions remain as to the activation, differentiation, and inhibitory functions of MDSCs. This review aims to summarize our current knowledge of MDSC subsets and suppressive functions in tissue-specific autoimmune disorders. We also describe the potential of MDSC-basedcell therapy for the treatment of autoimmune diseases and note some of hurdles facing the implementation of this therapy.