髓系来源的抑制性细胞在小鼠H22原位种植性肝癌中的表达及其意义

目的:比较小鼠H22原位种植性肝癌模型中髓系来源的抑制性细胞（MDSCs）和调节性T细胞（Tregs）的表达，确定主要的免疫抑制性细胞。并探讨主要免疫抑制性细胞在小鼠H22原位种植性肝癌模型中的意义。方法:建立小鼠H22原位种植性肝癌模型，用流式细胞术的方法比较外周血、脾脏、肿瘤组织中MDSCs、Tregs的比例。分析MDSCs与CD4+T细胞、CD8+T细胞、NK细胞、NKT细胞的相关性。通过脾脏切除的方法下调MDSCs的表达，观察对肿瘤存活的影响。结果:MDSCs的比例无论在外周血、脾脏还是肿瘤组织中都显著高于Tregs。MDSCs的比例与CD4+T细胞、CD8+T细胞、NK细胞、NKT细胞呈负相关。下调MDSCs的比例可以显著延长小鼠存活期。结论:小鼠H22原位种植性肝癌中主要的免疫抑制性细胞是MDSCs。MDSCs的高表达预示着不良的小鼠存活期。     

抗Gr-1抗体降低肺癌小鼠髓源性抑制细胞对CD8+T细胞数量和肿瘤生长的影响

目的探讨通过抗Gr-1抗体降低Lewis肺癌小鼠髓源性抑制细胞(MDSC)对肿瘤生长及对外周血、脾脏、肿瘤组织中CD8+ T细胞数量的影响。方法构建小鼠肺癌Lewis细胞荷瘤小鼠模型。每48 h腹腔注射抗Gr-1抗体降低MDSC(观察组), 以注射等量0.7% NaCl溶液的模型小鼠为对照组, 持续3周。接瘤第7、14、21天分别处死3只小鼠, 应用流式细胞仪动态监测各时间点小鼠外周血、脾脏、肿瘤组织中MDSC、CD8+ T细胞的比例;接瘤7 d后, 定时测量小鼠皮下肿瘤的长径、短径, 监测两组肿瘤大小。结果两组肿瘤体积均随时间延长而增长, 其中观察组上升趋势相对缓慢, 第20天观察组肿瘤体积较对照组小[(1 978±315)mm3比(1 356±432)mm3, P=0.001]。接瘤后第7、14、21天, 观察组小鼠外周血、脾脏、肿瘤组织中MDSC和CD8+ T细胞比例均低于对照组。两组小鼠外周血中MDSC比例随时间推移均呈上升趋势, 其中观察组小鼠MDSC比例上升趋势较对照组缓慢;两组外周血中CD8+ T细胞比例在第7天至第14天均呈现上升趋势, 且观察组上升趋势更明显, 第14...     

荷瘤小鼠脾脏过度增大的机制

目的研究H22荷瘤小鼠生长过程中脾脏过度增大的机制。方法通对小鼠脾指数与脾脏细胞总数进行相关性分析、检测脾细胞生长周期以及T、B淋巴细胞比例。结果小鼠脾指数与脾脏细胞总数呈显著正相关性(r=1.000,P<0.01);H22荷瘤小鼠与对照组小鼠脾脏细胞的细胞周期无明显差异;H22荷瘤小鼠与对照组小鼠相比脾脏总T淋巴细胞、CD8+T与CD4+T细胞比例增大(P<0.05),B细胞比例基本不变,CD4+ /CD8+ 减小。结论H22荷瘤小鼠脾脏增大与各类免疫细胞转移至脾脏后滞留有直接的关系,其中CD8+T细胞的积累最显著,脾脏的免疫抑制作用与CD8+T细胞有密切的关系。     

微波消融治疗对肝癌小鼠调节性 T 细胞的影响

目的：研究微波消融治疗荷肿瘤后小鼠的Treg和淋巴细胞亚群的变化,探讨微波消融治疗荷瘤小鼠后的机体免疫功能的变化.方法：建立H22荷瘤小鼠模型,分为荷瘤对照组和微波消融组.微波消融荷瘤小鼠肿瘤.流式细胞术检测脾脏中的CD4＋CD25＋T细胞、CD25＋FOXP3＋T细胞、CD4＋T细胞、CD8＋T细胞.结果：与荷瘤对照组相比,微波消融治疗后21天、28天组小鼠CD25＋FOXP3＋T细胞明显下降,差异有统计学意义（P＜0.05）,以术后28天下降更为明显（P＜0.01）.微波消融术后各组小鼠CD4＋/CD8＋比值明显增高（P＜0.05）.结论：微波消融治疗减低Tregs比例可能是热消融治疗提高机体抗肿瘤免疫作用的主要机制.微波消融治疗肿瘤后,Treg数量下降及功能降低,且CD4＋/CD8＋比值升高,提示了微波消融治疗肝癌可以改善机体的免疫状态.     

调节性T细胞与肿瘤

调节性T（regulatory T, Treg）细胞是一群具有抑制其他免疫细胞功能的负调控细胞，包括CD4+ Treg、CD8+ Treg、NKT Treg 和双阴性（double negative，DN）Treg细胞等四大类。研究显示，肿瘤微环境中Treg细胞数量升高，且这些升高的 Treg细胞能抑制抗肿瘤免疫、降低肿瘤免     

膀胱癌患者外周血髓系来源的抑制细胞的比例及其临床意义

目的分析髓系来源的抑制细胞（myeloid-derived suppressor cells,MDSC）在膀胱癌患者外周血中的分布,初步探讨其临床意义。方法采用流式细胞术检测62例膀胱癌患者及20例健康人外周血中MDSC的比例,分析MDSC比例与临床病理特征和CD4＋CD25high调节性T细胞（Treg）的关系。结果与正常对照（0.122±0.043）%相比,膀胱癌患者外周血中MDSC比例明显增加（0.679±0.438）%,二者差异有显著性（P〈0.01）;手术后,患者外周血中MDSC的比例明显下降,与术前比较有统计学意义（P〈0.05）;MDSC水平与膀胱癌肿瘤分期明显相关,而与肿瘤的分化程度和患者外周血Treg水平无显著相关（P〉0.05）。结论膀胱癌患者外周血MDSC细胞水平明显升高,可能与肿瘤免疫功能低下及肿瘤发生发展密切相关。     

小剂量环磷酰胺通过抑制调节性T细胞提高小鼠肝癌阿霉素化疗效果

目的 探讨小剂量环磷酰胺是否可以提高小鼠肝癌阿霉素化疗效果,并对其机制进行探讨.方法 建立C57BL/6J小鼠皮下肝癌模型,待肿瘤长至100～150mm3体积大小时备用.10只小鼠随机分为2组,对照组不处理,观察组以2 mg/只的剂量腹腔注射环磷酰胺(CTX),4天后以流式细胞仪检测小鼠脾脏CD4+、CD8+T细胞和CD4+CD25high Treg淋巴细胞比例.32只小鼠随机分为4组:①对照组(PBS);②环磷酰胺组(CTX);③阿霉素组(DOX);④环磷酰胺+阿霉素组(CTX+DOX);观察小鼠皮下肿瘤生长情况和小鼠的生存期.结果 应用小剂量CTX后荷瘤小鼠脾脏CD4+和CD8+T淋巴细胞的浸润分别由17.62%、16.03%上升到24.54%和25.41%(P<0.05),而Treg则由用药前的11.92%降低为用药后的5.36%(P<0.05).CTX组肿瘤生长和对照组相比无统计学差异(P>0.05).DOX组、CTX+DOX组肿瘤生长均显著受到抑制,以CTX+DOX组更为显著(P<0.05).DOX组生存期显著改善(P=0.027),联合应用CTX后生存期亦有显著捉高(P=0.018).结论 小剂量CTX可以抑制小鼠脾脏Treg浸润,改善机体免疫微环境,并可以增强肝癌阿霉素化疗的效果.免疫化疗治疗晚期肝癌具有一定的应用前景.     

肝癌患者脾脏免疫状态的研究

对16例肝癌病人外周血及脾静脉血T淋巴细胞亚群检测结果：1）肝癌患者较对照组外周血CD 3、CD 4细胞及CD4／CD8比值降低，CD 8细胞升高。2）肝癌患者脾静脉血较外周血CD 3、CD 4阳性细胞、CD4／CD8比例明显降低，CD 8显著升高。认为随着病程进展，脾脏不但不起正性免疫作用，反而转向负性免疫状态。同时，还对肝癌患者的脾脏手术问题进行了讨论。     

DC-CIK对胃癌合并腹水患者外周血CD4+CD25+调节性T细胞增殖及功能的影响

目的:探讨DC-CIK对胃癌合并腹水患者外周血CD4+CD25+调节性T胞(Treg细胞)比例及功能的影响。方法:60例胃癌合并腹水患者,于输注DC-CIK前1天及DC-CIK治疗结束后1周分别采集外周血。流式细胞术检测外周血Treg细胞的比例,RT-PCR法检测其Foxp3mRNA表达情况;将分选出的Treg细胞和CD4+CD25-T细胞分为单纯Treg细胞组（A组）、1∶1混合培养（B组）、单纯CD4+CD25-细胞组（C组）进行培养,3H-TdR掺入法检测Treg细胞抑制CD4+CD25-细胞增殖的能力。结果:治疗后外周血Treg细胞占CD4+T细胞的比例较疗前显著下降［(6.21±1.37)% vs (9.38±1.06)%,P＜0.05］。治疗后Treg细胞Foxp3mRNA表达水平较治疗前显著下降［(56.18±13.25)% vs (85.26±11.58)%,P＜0.05］。治疗后Treg对CD4+CD25-T细胞抑制增殖能力较治疗前明显下降［(37.31±4.16)% vs (48.92±5.25)%,P＜0.05］。结论:输注DC-CIK免疫治疗,可显著降低胃癌合并腹水患者外周血Treg细胞比例,下调Foxp3mRNA表达水平,降低Treg细胞免疫抑制功能,有利于诱导抗肿瘤免疫效应。     

冷冻消融对肝癌患者外周血CD4+CD25+调节T细胞影响的初步研究

目的探讨氩氦冷冻对肝癌外周血CD4 CD25 调节T细胞的影响及临床意义.方法原发性肝癌患者20例.其中Ⅱ期14例、Ⅲ期6例,分别采集氩氦冷冻治疗术前及术后1个月外周血,采用流式细胞术检测外周血T淋巴细胞亚群(CD3 T、CD4 T、CD8 T、CD4 T/CD8 T、NK细胞)及Treg细胞.结果肝癌Ⅲ期患者外周血Treg细胞占CD4 T细胞比例明显高于Ⅱ期患者(6.5%±1.2%、9.1%±2.0%,P=0.013).与氩氦冷冻治疗前比较治疗后1个月Treg细胞一定程度降低(8.2%±1.1%、7.7%±1.0%),但差异无显著性(P=0.052);CD4 T、CD4 T/CD8 T、NK细胞明显升高,CD8 T细胞降低(P＜0.05).结论肿瘤负荷可显著促进肝癌患者外周血Treg细胞分化.肝癌氩氦冷冻治疗后短期内Treg细胞比例轻度下降,T淋巴细胞亚群分布异常得到一定改善.     

Unmasking immunosurveillance against a syngeneic colon cancer by elimination of CD4+ NKT regulatory cells and IL-13

We have previously observed a novel role of natural killer T (NKT) cells in negative regulation of antitumor immune responses against an immunogenic regressor tumor expressing a transfected viral antigen. Here, we investigated whether hidden spontaneous antitumor immunosurveillance, in the absence of a vaccine, could be revealed by disruption of this negative regulatory pathway involving CD4+ NKT cells and interleukin-13 (IL-13), in a murine pulmonary metastasis model of a nontransfected, nonregressor, syngeneic tumor, the CT26 colon carcinoma. Lung metastases of CT26 were decreased in CD4+ T cell-depleted BALB/c mice, suggesting that CD4+ T cells were involved in negative regulation of antitumor responses. CD1-knock out (CD1-KO) mice, which have conventional CD4+ T cells and CD4+CD25+ regulatory T cells but lack CD1-restricted CD4+ NKT cells, were significantly resistant to lung metastasis of CT26. The metastases were not further decreased in CD4+ T cell-depleted CD1-KO mice, implying that CD4+ NKT cells might be the primary negative regulator of antitumor immune responses in BALB/c mice. CD8+ T cells were found to act as effectors in antitumor immune responses, since the inhibition of lung metastases observed in naive CD1-KO or CD4+ T cell-depleted mice was abrogated by depletion of CD8+ T cells. Lung metastases were significantly decreased by treatment of mice with an IL-13 inhibitor, but not by deficiency or inhibition of IL-4. Thus, even for a nonregressor tumor, immunosurveillance exists but is negatively regulated via CD4+ NKT cells possibly mediated by IL-13, and can be unmasked by removal of these negative regulatory components.     

Peripheral blood mononuclear cells of patients with breast cancer can be reprogrammed to enhance anti-HER-2/neu reactivity and overcome myeloid-derived suppressor cells

Two major barriers in the immunotherapy of breast cancer include tumor-induced immune suppression and the establishment of long-lasting immune responses against the tumor. Recently, we demonstrated in an animal model of breast carcinoma that expanding and reprogramming tumor-sensitized lymphocytes, ex vivo, yielded T memory (Tm) cells as well as activated CD25+ NKT cells and NK cells. The presence of activated CD25+ NKT and NK cells rendered reprogrammed T cells resistant to MDSC-mediated suppression, and adoptive cellular therapy (ACT) of reprogrammed lymphocytes protected the host from tumor development and relapse. Here, we performed a pilot study to determine the clinical applicability of our protocol using peripheral blood mononuclear cells (PBMCs) of breast cancer patients, ex vivo. We show that bryostatin 1 and ionomycin combined with IL-2, IL-7, and IL-15 can expand and reprogram tumor-sensitized PBMCs. Reprogrammed lymphocytes contained activated CD25+ NKT and NK cells as well as Tm cells and displayed enhanced reactivity against HER-2/neu in the presence of MDSCs. The presence of activated NKT cells was highly correlated with the rescue of anti-HER-2/neu immune responses from MDSC suppression. Ex vivo blockade experiments suggest that the NKG2D pathway may play an important role in overcoming MDSC suppression. Our results show the feasibility of reprogramming tumor-sensitized immune cells, ex vivo, and provide rationale for ACT of breast cancer patients.     

T cell subsets in peripheral blood and spleen in malignant hepatoma bearing rats

T cell subsets in rat peripheral blood and spleen were analysed longitudinally by flow cytometer and MAbs in a murine intrahepatic implanted tumor model. In the peripheral blood. OX-19+ cells (pan T cell) and W3/25+ cells (Th/i cell) were reduced with the tumor growth in hepatoma bearing rats, giving a significant difference as compared with the control group. No significant changes were found in OX-8+ cells (Ts/c cell). Hence, W3/25+/OX-8+ cell ratio in hepatoma bearing rats was lower than control group. Meanwhile, on day 17 following tumor implantation, in the hepatoma bearing rats with intrahepatic or peritoneal metastasis, there were less W3/25+ cells and more OX-8+ cells than those of hepatoma bearing rats without metastasis (P less than 0.01). In the spleen, the phenotypes of lymphocyte markers showed less OX-8+ cells and more OX-12+ cells (B cell) in hepatoma bearing rats. It was suggested that, in the tumor bearing host, not only was the T cell immune function inhibited, but also there was abnormal distribution of T cell subsets. It seems that there is a close relationship between tumor growth and its spread and Th cells reduction and Ts cells increase.     

Suppression of hepatocellular carcinoma growth via oral immune regulation towards tumor-associated antigens is associated with increased NKT and CD8+ lymphocytes

BACKGROUND: Oral immune regulation towards viral proteins was previously shown to modulate the anti-HBV immune response. Adoptive transfer of orally immunomodulated lymphocytes suppressed the growth of hepatocellular carcinoma (HCC) expressing HBsAg in athymic mice. NKT lymphocytes play a role in the defense against tumor growth. AIM: To evaluate the effect of oral immune regulation towards HCC-associated antigens or HBV proteins on growth of HBsAg-expressing HCC, and to determine the role of NKT lymphocytes in immune modulation. METHODS: Sublethally irradiated athymic Balb/c mice were injected with 10(7) human hepatoma cells followed 10 days later by transplantation of 2 x 10(6) splenocytes from naive donor mice. Immune modulation was performed via feeding of HCC-extracted proteins or HBV antigens (HBsAg + Pre S1 + Pre S2). The control group was fed with bovine serum albumin (BSA). Mice were followed for survival, tumor volume, and serum alpha-fetoprotein levels. To determine the role of NKT cells in tumor suppression, cytokine expression and FACS analysis for CD4+, CD8+, and NK1.1+ T lymphocyte subsets were performed. RESULTS: Oral immune regulation towards HCC-extracted proteins induced complete tumor suppression in recipient mice. Mortality rates were 0% in HCC-immune-regulated mice, compared with an 80% mortality rate using HBV antigens and a 100% mortality rate in control mice. Oral immune regulation towards HCC prevented weight loss. No visible tumor mass was observed in orally immune-regulated mice as compared with 112 mm(3) in controls. Serum alphaFP levels were 0.9, 378 and 1,358 ng/ml in HCC, HBV immune-regulated and controls, respectively. Immune regulation towards HCC antigens significantly increased the NK1.1+ T lymphocytes/CD4+ and CD8+/CD4+ ratios. IFNgamma production increased two-fold. CONCLUSION: Oral immune regulation towards HCC antigens effectively enhanced the anti-tumor immune response, thus suppressing the growth of HCC in mice. This effect was associated with an increased NKT,CD8+/CD4+ lymphocyte ratio and may be mediated via enhancement of IFNgamma production.     

Expression of activated CDC42 induces T cell apoptosis in thymus and peripheral lymph organs via different pathways

CDC42, a Ras-related small GTP binding protein, is involved in diverse cellular functions in lymphocytes. We generated transgenic mice expressing constitutively active murine CDC42 (Q61L) under the control of the human CD2 promoter. Transgenic mice showed smaller thymi with a dramatic reduction of CD4+CD8+, CD4+ and CD8+ thymocytes and with increase of CD4-CD8- thymocytes at CD25-CD44+ and CD25+ stage. A high percentage of the transgenic thymocytes were apoptotic, explaining the reduction of cellularity and size of the thymus. Mature T cells (TCR alphabeta+) in peripheral lymph organs, spleen and lymph node, were also dramatically reduced, and exhibited massive apoptosis. Expression of Fas and Fas ligand on both thymocytes and peripheral T cells was upregulated in transgenic mice, but the increased apoptosis in the thymus was independent of Fas (CD95), whereas peripheral spleen and lymph node T cell apoptosis was Fas dependent. Thus, activated CDC42 triggers distinct apoptotic pathways in thymocytes and peripheral T cells.     

Enhanced suppressive capacity of tumor‐infiltrating myeloid‐derived suppressor cells compared with their peripheral counterparts

Although the main site of action for myeloid‐derived suppressor cells (MDSCs) is most likely the tumor microenvironment, so far the study of these cells has been largely restricted to spleen‐derived MDSCs. In this study, we compared the suppressive capacity of splenic and tumor‐derived MDSCs in different subcutaneous mouse tumor models. We investigated which suppressive mechanisms were involved. Finally, we investigated whether MDSCs and regulatory T cells (T_reg) cooperate in the suppression of T‐cell responses. In all models, splenic granulocytic MDSCs (grMDSC) strongly suppress CD4⁺ T‐cell proliferation while the suppressive effect on CD8⁺ T cells is less pronounced. Splenic monocytic MDSCs (moMDSC) have a lower suppressive capacity, compared to grMDSC, on both CD4⁺ and CD8⁺ T‐cell proliferation. Both grMDSC and moMDSC isolated from the tumor have a much stronger suppressive activity compared to MDSCs isolated from the spleen of tumor‐bearing mice, associated with a higher NO₂^? production by the tumor‐derived moMDSC and arginase activity for both subsets. The expression of CD80 is also elevated on tumor‐derived grMDSC compared with their peripheral counterparts. Direct contact with tumor cells is required for the upregulation of CD80 and CD80⁺ MDSCs are more suppressive than CD80^? MDSCs. Coculture of T_reg and MDSCs leads to a stronger suppression of CD8⁺ T‐cell proliferation compared to the suppression observed by T_reg or MDSCs alone. Thus, we showed that tumor‐infiltrating MDSCs possess a stronger suppressive capacity than their peripheral counterparts and that various suppressive mechanisms account for this difference.     

髓源抑制性细胞与恶性肿瘤的研究进展

髓源抑制性细胞(myeloid derived suppressor cells,MDSCs)是一群异质性细胞,包括多种处于不同分化阶段的髓样细胞,如髓系祖细胞、未成熟的巨噬细胞、粒细胞、单核细胞、树突状细胞等。在荷瘤小鼠的血液、脾脏和肿瘤组织及肿瘤患者的外周血和肿瘤组织中存在大量MDSCs的扩增,与肿瘤的进展密切相关。恶性肿瘤来源的多种因子如粒细胞-巨噬细胞集落刺激因子（granulocyte-macrophage colony stimulating factor,GM-CSF）、白细胞介素（interleukin,IL）-6、S100钙结合蛋白A8/A9（S100 calcium binding protein A8/A9,S100A8/A9）等是导致MDSCs扩增的关键因素。MDSCs可通过抑制机体抗肿瘤免疫、上皮-间质转化(epithelial-mesenchymal transition,EMT）、侵袭、血管生成、转移前小生境形成等多种途径导致肿瘤发生发展。本文主要介绍MDSCs的亚群、功能、募集和活化机制,MDSCs作为预后标志物的价值以及当前靶向MDSCs的抗肿瘤治疗策略,以期加深对MDSCs与恶性肿瘤关系的认识。     

骨髓间充质干细胞预防手术后肿瘤肺转移动物模型研究

背景与目的:近年来研究发现,肿瘤患者术后髓系抑制细胞(myeloid-derived suppressor cells,MDSCs)较术前升高,且其促肿瘤血管生成和肿瘤生长作用增强,骨髓间充质干细胞(bone marrow mesenchymal stem cells,BMSCs)可抑制MDSCs活化与增殖.但围手术期MDSCs的变化与肿瘤术后转移的关系及BMSCs能否通过抑制MDSCs预防手术后肿瘤转移尚不清楚.该研究拟探讨围手术期MDSCs变化与手术后肿瘤转移的相关性及BMSCs对围手术期MDSCs和手术后肿瘤转移的影响.方法:C57BL/6小鼠经尾静脉注射LLC细胞后分为4组:对照组(C组)、麻醉组(A组)、麻醉后开腹组(AL组)及麻醉后开腹并肝叶切除组(ALH组).AL组小鼠手术后分为2组:术后无治疗组(AL1组)和术后给予同系BMSCs治疗组(ALB组).流式细胞术检测小鼠外周血单个核细胞(peripheral blood mononuclear cells,PBMCs)中Gr-1+CD11b+细胞的含量;第14天计数小鼠肺表面转移灶.小鼠骨髓细胞体外诱导MDSCs体系中加入BMSCs共培养的方法探讨BMSCs对MDSCs生成的影响.结果:与C、A组相比,AL和ALH组小鼠肺转移灶显著增多(P<0.01);且ALH组较AL组显著增多(P<0.05).手术后AL和ALH组小鼠PBMCs中Gr-1+CD11b+细胞与C、A组相比显著升高;与AL组比较,ALH组Gr-1+CD11b+细胞显著升高.第14天,AL及ALB组小鼠肺表面转移灶数量分别为38.00±9.57和6.54±1.49,差异有统计学意义(P<0.01).ALB组小鼠PBMCs中Gr-1+CD11b+细胞与AL1组相比明显降低.小鼠骨髓细胞体外诱导MDSCs体系中加入BMSCs可显著抑制MDSCs的活化和增殖.结论:手术应激诱导MDSCs并促肿瘤肺转移形成,BMSCs可以抑制MDSCs的生成进而抑制手术后肺转移形成.     

AZD1480 delays tumor growth in a melanoma model while enhancing the suppressive activity of myeloid-derived suppressor cells

AZD1480 is a potent, competitive small-molecule inhibitor of JAK1/2 kinase which inhibits STAT3 phosphorylation and tumor growth. Here we investigated the effects of AZD1480 on the function of different immune cell populations in a melanoma model. When MO4 tumor-bearing mice were treated with AZD1480 we observed a strong inhibition of tumor growth as well as a prolonged survival. Moreover, a significant decrease in the percentage of myeloid-derived suppressor cells (MDSCs) was observed after treatment with AZD1480. However, AZD1480 enhanced the suppressive capacity of murine MDSCs while at the same time impairing the proliferative as well as the IFN-γ secretion capacity of murine T cells. The addition of AZD1480 to co-cultures of human MDSCs and T cells does not affect the suppressive activity of MDSCs but it does reduce the IFN-γ secretion and the proliferative capacity of T cells. We showed that although AZD1480 has the ability to delay the tumor growth of MO4 tumor-bearing mice, this drug has detrimental effects on several aspects of the immune system. These data indicate that systemic targeting of the JAK/STAT pathway by JAK1/2 inhibition can have divergent effects on tumor growth and anti-tumor immune responses.