Mechanisms of myeloid-derived suppressor cell-mediated immunosuppression in colorectal cancer and related therapies

Severe immunosuppression is a hallmark of colorectal cancer(CRC).Myeloid-derived suppressor cells(MDSCs),one of the most abundant components of the tumor stroma,play an important role in the invasion,metastasis,and immune escape of CRC.MDSCs create an immunosuppressive microenvironment by inhibiting the proliferation and activation of immunoreactive cells,including T and natural killer cells,as well as by inducing the proliferation of immunosuppressive cells,such as regulatory T cells and tumor-associated macrophages,which,in turn,promote the growth of cancer cells.Thus,MDSCs are key contributors to the emergence of an immunosup-pressive microenvironment in CRC and play an important role in the breakdown of antitumor immunity.In this narrative review,we explore the mechanisms through which MDSCs contribute to the immunosuppressive microenvironment,the current therapeutic approaches and technologies targeting MDSCs,and the therapeutic potential of modulating MDSCs in CRC treatment.This study provides ideas and methods to enhance survival rates in patients with CRC.

Continuous activation of polymorphonuclear myeloid-derived suppressor cells during pregnancy is critical for fetal development

The maternal immune system is vital in maintaining immunotolerance to the semiallogeneic fetus for a successful pregnancy.Although studies have shown that myeloid-derived suppressor cells(MDSCs)play an important role in maintaining feto-maternal tolerance,little is known about the role of MDSCs in pregnancies with intrauterine growth retardation(IUGR).Here,we reported that the activation of polymorphonuclear myeloid-derived suppressor cells(PMN-MDSCs)during pregnancy was closely associated with fetal growth.In humans,class E scavenger receptor 1(SR-E1),a distinct marker for human PMN-MDSCs,was used to investigate PMN-MDSC function during pregnancy.Continuous activation of SR-E1+PMN-MDSCs was observed in all stages of pregnancy,accompanied by high cellular levels of ROS and arginase-1 activity,mediated through STAT6 signaling.However,SR-E1+PMN-MDSCs in pregnancies with IUGR showed significantly lower suppressive activity,lower arginase-1 activity and ROS levels,and decreased STAT6 phosphorylation level,which were accompanied by an increase in inflammatory factors,compared with those in normal pregnancies.Moreover,the population of SR-E1+PMN-MDSCs was negatively correlated with the adverse outcomes of newborns from pregnancies with IUGR.In mice,decreases in cell population,suppressive activity,target expression levels,and STAT6 phosphorylation levels were also observed in the pregnancies with IUGR compared with the normal pregnancies,which were rescued by the adoptive transfer of PMN-MDSCs from pregnant mice.Interestingly,the growth-promoting factors(GPFs)secreted by placental PMN-MDSCs in both humans and mice play a vital role in fetal development.These findings collectively support that PMN-MDSCs have another new role in pregnancy,which can improve adverse neonatal outcomes.

Aryl hydrocarbon receptor activation drives polymorphonuclear myeloid-derived suppressor cell response and efficiently attenuates experimental Sjögren’s syndrome

Myeloid-derived suppressor cells(MDSCs)comprise heterogeneous myeloid cell populations with immunosuppressive capacity that contribute to immune regulation and tolerance induction.We previously reported impaired MDSC function in patients with primary Sjögren’s syndrome(pSS)and mice with experimental SS(ESS).However,the molecular mechanisms underlying MDSC dysfunction remain largely unclear.In this study,we first found that aryl hydrocarbon receptor(AhR)was highly expressed by human and murine polymorphonuclear MDSCs(PMN-MDSCs).Indole-3-propionic acid(IPA),a natural AhR ligand produced from dietary tryptophan,significantly promoted PMN-MDSC differentiation and suppressive function on CD4^(+)T cells.In contrast,feeding a tryptophan-free diet resulted in a decreased PMN-MDSC response,a phenotype that could be reversed by IPA supplementation.The functional importance of PMN-MDSCs was demonstrated in ESS mice by using a cell-depletion approach.Notably,AhR expression was reduced in PMN-MDSCs during ESS development,while AhR antagonism resulted in exacerbated ESS pathology and dysregulated T effector cells,which could be phenocopied by a tryptophan-free diet.Interferon regulatory factor 4(IRF4),a repressive transcription factor,was upregulated in PMN-MDSCs during ESS progression.Chromatin immunoprecipitation analysis revealed that IRF4 could bind to the promoter region of AhR,while IRF4 deficiency markedly enhanced AhR-mediated PMN-MDSC responses.Furthermore,dietary supplementation with IPA markedly ameliorated salivary glandular pathology in ESS mice with restored MDSC immunosuppressive function.Together,our results identify a novel function of AhR in modulating the PMN-MDSC response and demonstrate the therapeutic potential of targeting AhR for the treatment of pSS.

Circulating myeloid-derived suppressor cells in patients with pancreatic cancer

BACKGROUND： Myeloid-derived suppressor cells （MDSCs） are heterogeneous cell types that suppress T-cell responses in cancer patients and animal models, some MDSC subpopulations are increased in patients with pancreatic cancer. The present study was to investigate a specific subset of MDSCs in patients with pancreatic cancer and the mechanism of MDSCs increase in these patients. METHODS： Myeloid cells from whole blood were collected from 37 patients with pancreatic cancer, 17 with cholangiocarcinoma, and 47 healthy controls. Four pancreatic cancer cell lines were co- cultured with normal peripheral blood mononudear cells （PBMCs） to test the effect of tumor cells on the conversion of PBMCs to MDSCs. Levels of granulocyte-macrophage colony-stimulating factor （GM-CSF） and arginase activity in the plasma of cancer patients were analyzed by enzyme-linked immunosorbent assay. RESULTS： CD14＋/CD11b＋/HLA-DR MDSCs were increased in patients with pancreatic or bile duct cancer compared with those in healthy controls, and this increase was correlated with clinical cancer stage. Pancreatic cancer cell lines induced PBMCs to MDSCs in a dose-dependent manner. GM-CSF and arginase activity levels were significantly increased in the se rum of patients with pancreatic cancer. CONCLUSIONS： MDSCs were tumor related： tumor cells induced PBMCs to MDSCs in a dose-dependent manner and circulating CD14＋/CD11b＋/HLA-DR- MDSCs in pancreatic cancer patients were positively correlated with tumor burden. MDSCs might be useful markers for pancreatic cancer detection and progression.

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.

Cyclooxygenase-2 Blockade Inhibits Accumulation and Function of Myeloid-derived Suppressor Cells and Restores T Cell Response after Traumatic Stress

Myeloid-derived suppressor cells （MDSCs） play a crucial role in T cell dysfunction, which is related to poor outcome in patients with severe trauma. Cyclooxygenase-2 （Cox-2） contributes to immune disorder in trauma and infection via production of prostaglandin E2. However, the role of Cox-2 in the accumulation and function of MDSCs after traumatic stress has not been fully elucidated. In the present study, we treated murine trauma model with NS398, a selective Cox-2 inhibitor. Then the percentages of CD1 lb＋/Gr-l＋ cells, proliferation and apoptosis of CD4＋ T cells were determined. Ar- ginase activity and arginase-1 （Arg-1） protein expression of splenic CDllb＋/Gr-I＋ cells, and de- layed-type hypersensitivity （DTH） response were analyzed. The results showed that Cox-2 blockade significantly decreased the percentages of CD1 lb＋/Gr-l＋ cells in the spleen and bone marrow 48 and 72 h after traumatic stress. NS398 inhibited arginase activity and down-regulated the Arg-1 expression of splenic CD1 lb＋/Gr-l＋ ceils. Moreover, NS398 could promote proliferation and inhibit apoptosis of CD4＋ T cells. It also restored DTH response of traumatic mice. Taken together, our data revealed that Cox-2 might play a pivotal role in the accumulation and function of MDSC after traumatic stress.

Correlation between circulating myeloid-derived suppressor cells and Th17 cells in esophageal cancer

AIM: To perform a comprehensive investigation into the potential correlation between circulating myeloidderived suppressor cells (MDSCs) and Th17 cells in esophageal cancer (ECA). METHODS: A total of 31 patients newly diagnosed with ECA and 26 healthy subjects were included in the current study. The frequencies of MDSCs and Th17 cells in peripheral blood were determined by flow cytometry. The mRNA expression of cytokines, arginase 1 (Arg1) and inducible NO synthase (iNOS) in peripheral blood mononuclear cells (PBMCs) and plasma Arg1 were assessed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. RESULTS: There was an increased prevalence of MDSCs in the peripheral blood from ECA patients (15.21% ± 2.25%) when compared with healthy control (HC) (1.10% ± 0.12%, P < 0.0001). The plasma levels of Arg1 in ECA patients were significantly higher than those in HC (28.28 ± 4.10 ng/mL vs 9.57 ± 1.51 ng/ mL, P=0.0003). iNOS mRNA levels in the peripheral blood of ECA patients also showed a threefold increase compared with HC (P=0.0162). The frequencies of Th17 cells (CD4 + IL-17A + ) were significantly elevated in ECA patients versus HC (3.50% ± 0.33% vs 1.82% ± 0.19%, P=0.0001). Increased mRNA expression of IL-17 and ROR-γt was also observed in ECA patients compared with HC (P=0.0041 and P=0.0004, respectively), while the mRNA expression of IL-6 and tumor necrosis factor-α (TNF-α) showed significant decreases (P=0.0049 and P < 0.0001, respectively). No obvious correlations were found between the frequencies of MDSCs and Th17 cells in the peripheral blood from ECA patients(r=-0.1725, P=0.3534). Arg1 mRNA levels were positively correlated with levels of IL-6 (r=0.6404, P=0.0031) and TNF-α (r=0.7646, P=0.0001). Similarly, iNOS mRNA levels were also positively correlated with levels of IL-6 (r=0.6782, P=0.0007) and TNF-α (r=0.7633, P < 0.0001). CONCLUSION: This study reveals the relationship between circulating MDSCs and Th17 cells, which may lead to new immunotherapy approaches for ECA based on the associated metabolites and cytokines.

Changes in the frequency of myeloid-derived suppressor cells after transarterial chemoembolization with gelatin sponge microparticles for hepatocellular carcinoma

Purpose: A series of clinical studies have established the safety and efficacy of transcatheter arterial chemoembolization(TACE) with gelatin sponge microparticles(GSMs) in treating hepatocellular carcinoma(HCC). HCC can lead to obvious necrosis inside tumors, especially larger ones, although it is unclear whether such necrotic tumor tissue can induce favorable immune reactions against the tumor. Myeloid-derived suppressor cells(MDSCs)have immunosuppressive functions and are currently considered a very important cell type affecting tumor immunity. This study observed changes in MDSC frequency in peripheral blood before and after GSM–TACE to evaluate the effect on the immune function of HCC patients.Methods: Eight patients diagnosed with HCC underwent GSM–TACE treatment in the Hepatobiliary Interventional Department of Beijing Tsinghua Chang Gung Hospital, Beijing, China;we followed up with the patients over a period of 30 days post-surgery. We used flow cytometry(FCM) to quantify the frequency of MDSCs in peripheral blood before TACE, 10 days after surgery and 30 days after surgery.Results: MDSC frequency after GSM–TACE had a significant downward trend. Pre-TACE, it was 30.73% ? 11.93%,decreasing to 18.60% ? 11.37% at 10 days after operation. This decrease was not statistically significant(P > 0.05). MDSC frequency was even lower 30 days after TACE(7.63% ? 7.32%) than at 10 days after TACE(P < 0.05), and there was a significant difference compared with pre-TACE(P < 0.001). We evaluated tumor response at 30 days after GSM–TACE according to the Modified Response Evaluation Criteria in Solid Tumors(mRECIST), and all eight patients showed partial response(PR).Conclusion: Our results confirmed that GSM–TACE was beneficial for improving anti-tumor immunity in the treatment of HCC.

Amplification of Functional Myeloid-derived Suppressor Cells during Stem Cell Mobilization Induced by Granulocyte Colony-stimulation-factor

The effects of granulocyte colony-stimulation-factor （G-CSF） on stem cell mobilization and its impact on the amplification of myeloid-derived suppressor cells （MDSCs） of donor mice were ex- amined. A mouse model of stem cell mobilization was established by consecutive subcutaneous injec- tion of 100 μg/kg G-CSF for 5 days. The blood from the donor mice was routinely examined during mobilization. Stem cells and MDSCs were analyzed by flow cytometry. The immunosuppressive mole- cules derived from MDSCs in serum and spleen, including hydrogen dioxide （H202） and nitric oxide （NO）, and the activity of nitric oxide synthase （NOS） were determined during the mobilization. Apop- tosis of T lymphocytes was assessed by using Annexin-V/PI. During stem cell mobilization, the number of lymphocytes and white blood cells in the peripheral blood was increased, and peaked on the 4th day. The number of stem cells in G-CSF-treated mice was significantly greater than that in controls （P〈0.01）. The expansions of MSDCs were also observed after G-CSF mobilization, with a more notable rate of growth in the peripheral blood than in the spleen. The activity of NOS and the production of NO were increased in the donor mice, and the serum H202 levels were approximately 4-fold greater than the con- trois. Consequently, apoptosis of T lymphocytes was increased and showed a positive correlation with the elevated percentage of MDSCs. It was concluded that G-CSF could provide sufficient peripheral blood stem cells for transplantation. Exogenous administration of G-CSF caused the accumulation of MDSCs in the peripheral blood and the spleen, which could lead to apoptosis ofT lymphocytes and may offer a new strategy for the prevention and treatment of graft versus host disease.

Myeloid-derived Suppressor Cells Activate Liver Natural Killer Cells in a Murine Model in Uveal Melanoma

Objective Elevated myeloid-derived suppressor cells(MDSCs)in many malignancies are associated with the increased risk for metastases and poor prognosis.Therefore,a mouse model of intraocular melanoma was established to explore how MDSCs influence liver metastases.Methods In this study,murine B16LS melanoma cells were transplanted into the posterior compartment(PC)of the eye of C57BL/6 mice.Leucocytes from the liver of naive mice and mice bearing melanoma liver metastasis were isolated using isotonic Percoll centrifugation,examined by flow cytometry for their expression of Gr1,CD11b,F4/80,RAE-1,and Mult-1,and further isolated for MDSCs and natural killer(NK)cells.The effects of MDSCs on NK cells were tested by coculturing and assessing the ability of NK cells to produce interferon-gamma(IFN-γ)by ELISA and NK cell cytotoxicity by 3H-thymidine incorporation assay.The impact of IFN-γon liver metastases was examined via selectively depleting IFN-γin vivo.Results The results showed that mice with liver metastases had increased levels of CD11b+Gr1+F4/80+as well as CD11b+Gr1+F4/80−MDSCs.MDSCs significantly enhanced the generation of IFN-γtogether with the cytotoxicity of the NK cells.Furthermore,these effects were cell-cell contact-dependent.Although IFN-γwas not of a toxic nature to the melanoma cells,it profoundly inhibited B16LS cell proliferation.Depleting IFN-γin vivo led to increased liver metastases.Conclusion All these findings first revealed that MDSCs accumulated in liver metastasis of intraocular melanoma could activate the NK cells to produce an effective anti-tumor immune response.Thus,the MDSCs’performance in different tumor models would need more investigation to boost current immunotherapy modalities.

Myeloid-derived suppressor cells in gastrointestinal cancers:A systemic review

Gastrointestinal(GI)cancers are one of the most common malignancies worldwide,with high rates of morbidity and mortality.Myeloid-derived suppressor cells(MDSCs)are major components of the tumor microenvironment(TME).MDSCs facilitate the transformation of premalignant cells and play roles in tumor growth and metastasis.Moreover,in patients with GI malignancies,MDSCs can lead to the suppression of T cells and natural killer cells.Accordingly,a better understanding of the role and mechanism of action of MDSCs in the TME will aid in the development of novel immune-targeted therapies.

GM3-containing nanoparticles in immunosuppressed hosts:Effect on myeloid-derived suppressor cells

Cancer vaccines to date have not broadly achieved a significant impact on the overall survival of patients. The negative effect on the immune system of the tu-mor itself and conventional anti-tumor treatments such as chemotherapy is, undoubtedly, a key reason for these disappointing results. Myeloid-derived suppres-sor cells （MDSCs） are considered a central node of the immunosuppressive network associated with tumors. These cells inhibit the effector function of natural killer and CD8＋ T cells, expand regulatory T cells and can differentiate into tumor-associated macrophages within the tumor microenvironment. Thus, overcoming the suppressive effects of MDSCs is likely to be criti-cal for cancer immunotherapy to generate effective anti-tumor immune responses. However, the capacity of cancer vaccines and particularly their adjuvants to overcome this inhibitory population has not been well characterized. Very small size proteoliposomes （VSSP） is a nanoparticulated adjuvant specifcally designed to be formulated with vaccines used in the treatment of immunocompromised patients. This adjuvant contains immunostimulatory bacterial signals together with GM3 ganglioside. VSSP promotes dendritic cell maturation, antigen cross-presentation to CD8＋ T cells, Th1 polar-ization, and enhances CD8＋ T cell response in tumor-free mice. Currently, four cancer vaccines using VSSP as the adjuvant are in Phase？Ⅰ？and Ⅱ clinical trials. In this review, we summarize our work characterizing the unique ability of VSSP to stimulate antigen-specifc CD8＋ T cell responses in two immunocompromised sce-narios; in tumor-bearing mice and during chemother-apy-induced leukopenia. Particular emphasis has been placed on the interaction of these nanoparticles with MDSCs, as well as comparison with other cancer vac-cine adjuvants currently in preclinical or clinical studies.

Intermittent fasting boosts antitumor immunity by restricting CD11b^(+)Ly6C^(low)Ly6G^(low) cell viability through glucose metabolism in murine breast tumor model

Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy.However,it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting.Herein we observed that two cycles of fasting treatment significantly inhibited breast tumor growth and lung tissue metastasis,as well as prolonged overall survival in mice bearing 4T1 and 4T07 breast cancer.During this process,both the immunosuppressive monocytic-(M-)and granulocytic-(G-)myeloid-derived suppressor cell(MDSC)decreased,accompanied by an increase in interleukin(IL)7R^(+)and granzyme B^(+)T cells in the tumor microenvironment.Interestingly,we observed that Ly6G^(low)G-MDSC sharply decreased after fasting treatment,and the cell surface markers and protein mass spectrometry data showed potential therapeutic targets.Mechanistic investigation revealed that glucose metabolism restriction suppressed the splenic granulocytemonocyte progenitor and the generation of colony-stimulating factors and IL-6,which both contributed to the accumulation of G-MDSC.On the other hand,glucose metabolism restriction can directly induce the apoptosis of Ly6G^(low)G-MDSC,but not Ly6G^(high)subsets.In summary,these results suggest that glucose metabolism restriction induced by fasting treatment attenuates the immune-suppressive milieu and enhances the activation of CD3^(+)T cells,providing potential solutions for enhancing immune-based cancer interventions.

Increased frequency and clinical significance of myeloidderived suppressor cells in human colorectal carcinoma

AIM： To investigate the frequency and clinical signifi- cance of the myeloid-derived suppressor cells （MDSC） in human colorectal carcinoma （CRC）. METHODS： Samples of peripheral blood and tumor tis- sue from 49 CRC patients were analyzed. Mononuclear cells were isolated by FicolI-Hypaque density gradient centrifugation and were subjected to a flow cytometry- based immunophenotypic analysis. RESULTS： A considerable increase in the percentage of CD33＋HLA-DR MDSCs was observed in the periph- eral blood （1.89% ：1= 0.75%） and tumor tissues （2.99%±1.29%） of CRC patients as compared with that in theperipheral blood of healthy controls （0.54%±0.35%）. This expanded CD33＋HLA-DR subset exhibited imma- ture myeloid cell markers, but not lineage markers, and showed up-regulation of CD18/CD11b expression as compared with the MDSCs from healthy donors. Fur- ther studies showed that the MDSC proportion in CRC peripheral blood was correlated with nodal metastasis （P = 0.023）, whereas that in tumor tissues was cor- related with nodal/distant metastasis （P = 0.016/P = 0.047） and tumor stage （P = 0.028）, suggesting the involvement of MDSCs in CRC tumor development. CONCLUSION： Characterization of MDSCs in CRC sug- gests the clinical significance of circulating and tumor- infiltrating MDSCs and may provide new insights into the CRC immunotherapy targeting MDSCs.

Single-cell transcriptome profiling of sepsis identifies HLA-DR^(low)S100A^(high)monocytes with immunosuppressive function

Background Sustained yet intractable immunosuppression is commonly observed in septic patients,resulting in aggravated clinical outcomes.However,due to the substantial heterogeneity within septic patients,precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking.Methods We adopted cross-species,single-cell RNA sequencing(scRNA-seq)analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis.Flow cytometry,laser scanning confocal microscopy(LSCM)imaging and Western blotting were applied to identify the presence of S100A9^(+)monocytes at protein level.To interrogate the immunosuppressive function of this subset,splenic monocytes isolated from septic wild-type or S100a9^(–/–)mice were co-cultured with naive CD4^(+)T cells,followed by proliferative assay.Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage.Results scRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis,for which distinct monocyte subsets were enriched in disparate subclusters of septic patients.We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR(HLA-DR),which were prominently enriched in septic patients and might exert immunosuppressive function.By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments,we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice,corresponding to HLA-DR^(low)S100A^(high)monocytes in human sepsis.Moreover,we found that S100A9^(+)monocytes exhibited profound immunosuppressive function on CD4^(+)T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression.Conclusions This study identifies HLA-DR^(low)S100A^(high)monocytes correlated with immunosuppressive state upon septic challenge,inhibition of which can markedly mitigate sepsis-induced immune depression,thereby providing a novel therapeutic strategy for the management of sepsis.

ACAT1 deficiency in myeloid cells promotes glioblastoma progression by enhancing the accumulation of myeloid-derived suppressor cells

Glioblastoma(GBM)is a highly aggressive and lethal brain tumor with an immunosuppressive tumor microenvironment(TME).In this environment,myeloid cells,such as myeloid-derived suppressor cells(MDSCs),play a pivotal role in suppressing antitumor immunity.Lipometabolism is closely related to the function of myeloid cells.Here,our study reports that acetyl-CoA acetyltransferase 1(ACAT1),the key enzyme of fatty acid oxidation(FAO)and ketogenesis,is significantly downregulated in the MDSCs infiltrated in GBM patients.To investigate the effects of ACAT1 on myeloid cells,we generated mice with myeloid-specific(LyzM-cre)depletion of ACAT1.The results show that these mice exhibited a remarkable accumulation of MDSCs and increased tumor progression both ectopically and orthotopically.The mechanism behind this effect is elevated secretion of C-X-C motif ligand 1(CXCLI)of macrophages(Mo).Overall,our findings demonstrate that ACAT1 could serve as a promising drug target for GBM by regulating the function of MDSCs in the TME.

APE1通过免疫抑制性肿瘤微环境介导结肠炎相关结直肠癌的发生发展

目的探讨脱嘌呤/脱嘧啶核酸内切酶1(apurinic/apyrimidinic endonuclease 1,APE1)在慢性肠道炎症向结肠炎相关性结直肠癌(colitis-associated colorectal cancer,CAC)转化过程中的调控机制。方法将C64S点突变纯合子(APE1^(C64S))和野生型(APE1^(WT))小鼠分别按随机数字表法分为实验组与对照组,实验组应用氧化偶氮甲烷(azoxymethane,AOM)及葡聚糖硫酸钠盐(dextran sulfate sodium salt,DSS)溶液构建CAC体内模型,采用免疫组化及多重免疫荧光分析各组小鼠结肠组织APE1表达及免疫细胞浸润情况。通过慢病毒转染构建APE1稳定敲低的小鼠结肠癌MC38细胞系,并对APE1^(WT)与APE1^(C64S)小鼠进行皮下荷瘤实验以确定肿瘤细胞来源的APE1导致免疫抑制性肿瘤微环境,采用免疫组化及多重免疫荧光分析荷瘤标本APE1、趋化因子(C-X-C基序)配体1[chemokine(C-X-C motif)ligand 1,CXCL1]表达及免疫细胞浸润情况。对来自陆军特色医学中心的1名28岁女性CAC患者的肿瘤标本采用免疫组化及多重免疫荧光分析肿瘤及邻近炎症组织中APE1、CXCL1的表达及免疫细胞浸润情况。结果与对照组及APE1^(WT)实验组相比,APE1^(C64S)实验组小鼠的疾病活动指数及肿瘤形成数量明显降低,多形核髓源抑制细胞(polymorphonuclear myeloid-derived suppressor cells,PMN-MDSCs)浸润显著减少,CD4^(+)及CD8^(+)T细胞显著增多(P<0.05)。APE1^(WT)与APE1^(C64S)皮下荷瘤小鼠肿瘤生长及各免疫细胞差异无统计学意义;而使用敲低APE1的肿瘤细胞进行荷瘤实验,发现肿瘤生长明显抑制,PMN-MDSCs浸润减少,同时CD4^(+)及CD8^(+)T细胞显著增多(P<0.05)。在CAC患者肿瘤组织中APE1高表达、PMN-MDSCs浸润增加,CD8^(+)T细胞在肿瘤组织中较炎症组织浸润显著减少(P<0.05)。结论肿瘤细胞中APE1的氧化还原功能可促进PMN-MDSCs肿瘤浸润,同时减少T细胞的数量,从而形成免疫抑制性肿瘤微环境介导CAC的发生发展。

Contribution of myeloid-derived suppressor cells to tumor-induced immune suppression,angiogenesis,invasion and metastasis

Growing evidence suggests that myeloid-derived suppressor cells （MDSCs）,which have been named ＂immature myeloid cells＂ or ＂myeloid suppressor cells＂ （MSCs）,play a critical role during the progression of cancer in tumor-bearing mice and cancer patients.As their name implies,these cells are derived from bone marrow and have a tremendous potential to suppress immune responses.Recent studies indicated that these cells also have a crucial role in tumor progression.MDSCs can directly incorporate into tumor endothelium.They secret many pro-angiogenic factors as well.In addition,they play an essential role in cancer invasion and metastasis through inducing the production of matrix metalloproteinases （MMPs）,chemoattractants and creating a pre-metastatic environment.Increasing evidence supports the idea that cancer stem cells （CSCs） are responsible for tumorigenesis,resistance to therapies,invasion and metastasis.Here,we hypothesize that CSCs may ＂hijack＂ MDSCs for use as alternative niche cells,leading to the maintenance of stemness and enhanced chemo-and radio-therapy resistance.The countermeasure that directly targets to MDSCs may be useful for against angiogenesis and preventing cancer from invasion and metastasis.Therefore,the study of MDSCs is important to understand tumor progression and to enhance the therapeutic efficacy against cancer.

Hepatic immune tolerance induced by hepatic stellate cells

The liver, which is a metabolic organ, plays a pivotal role in tolerance induction. Hepatic stellate cells(Hp SCs), which are unique non-parenchymal cells, exert potent immunoregulatory activity during cotransplantation with allogeneic islets effectively protecting the islet allografts from rejection. Multiple mechanisms participate in the immune tolerance induced by Hp SCs, including the marked expansion of myeloid-derived suppressor cells(MDSCs), attenuation of effector T cell functions and augmentation of regulatory T cells. Hp SC conditioned MDSC-based immunotherapy has been conducted in mice with autoimmune disease and the results show that this technique may be promising. This article demonstrates how Hp SCs orchestrate both innate immunity and adaptive immunity to build a negative network that leads to immune tolerance.

Emergence of immunotherapy as a novel way to treat hepatocellular carcinoma

Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma(HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from noncancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.