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Yujia Peng Yuyin Fu Hong Liu Shengyan Zhao Han Deng Xiaohua Jiang Qinhuai Lai Ying Lu Cuiyu Guo Guangbing Zhang Yong Luo Yuxi Wang Lantu Gou Jinliang Yang 《International journal of cancer. Journal international du cancer》2024,154(7):1285-1297
CD25, also known as the interleukin-2 receptor α chain (IL-2Rα), is highly expressed on regulatory T cells (Tregs), but relatively lower on effector T cells (Teffs). This makes it a potential target for Treg depletion, which can be used in tumor immunotherapy. However, marketed anti-CD25 antibodies (Basiliximab and Daclizumab) were originally developed as immunosuppressive drugs to prevent graft rejection, because these antibodies can block IL-2 binding to CD25 on Teffs, which in turn destroys the function of Teffs. Recent studies have shown that non-IL-2-blocking anti-CD25 antibodies have displayed exciting antitumor effects. Here, we screened out a non-IL-2-blocking anti-CD25 monoclonal antibody (mAb) 7B7 by hybridoma technology, and confirmed its antitumor activity via depleting Tregs in a CD25 humanized mouse model. Subsequently, we verified that the humanized 7B7, named as h7B7-15S, has comparable activities to 7B7, and that its Treg depletion is further increased when combined with anti-CTLA-4, leading to enhanced remodeling of the tumor immune microenvironment. Moreover, our findings reveal that the Fab form of h7B7-15S has the ability to deplete Tregs, independent of the Fc region. Taken together, our studies expand the application of anti-CD25 in tumor immunotherapy and provide insight into the underlying mechanism. 相似文献
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Hiroyoshi Nishikawa Shimon Sakaguchi 《International journal of cancer. Journal international du cancer》2010,127(4):759-767
Recent studies have revealed that Foxp3+CD25+CD4+ regulatory T cells (Tregs), which are physiologically engaged in the maintenance of immunological self‐tolerance, play critical roles for the control of antitumor immune responses. For example, a large number of Foxp3+Tregs infiltrate into tumors, and systemic removal of Foxp3+Tregs enhances natural as well as vaccine‐induced antitumor T‐cell responses. Tregs are recruited to tumor tissues via chemokines, such as CCL22 binding to CCR4 expressed by Tregs. They appear to expand and become activated in tumor tissues and in the draining lymph nodes by recognizing tumor‐associated antigens as well as normal self‐antigen expressed by tumor cells. These results indicate that cancer vaccines targeting tumor‐associated self‐antigens may potentially expand/activate Tregs and hamper effective antitumor immune responses, and that tumor immunity can therefore be enhanced by depleting Tregs, attenuating Treg suppressive function, or rendering effector T cells refractory to Treg‐mediated suppression. Recent attempts have indeed demonstrated that combinations of monoclonal antibodies capable of modulating Treg functions synergistically enhance antitumor activity and are more effective than a single monoclonal antibody therapy. Combination therapy targeting a variety of molecules expressed in antigen‐presenting cells, effector T cells and Tregs is envisaged to be a promising anticancer immunotherapy. 相似文献
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调节性T细胞是具有免疫抑制功能的T细胞亚群,在维持机体免疫平衡和自身免疫耐受中起重要作用,最新研究表明,FOXP3^+CD25^+CD4^+调节性T细胞在各种肿瘤患者的外周血与肿瘤组织内大量表达,并且与肿瘤发生、发展及预后有明显的关系。 相似文献
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Tumor-derived CD4+CD25+ Tregs Inhibit the Maturation and Antigen-Presenting Function of Dendritic Cells
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《Asian Pacific journal of cancer prevention》2015,16(7):2665-2669
CD4+CD25+regulatory T cells (Tregs) play a key role in regulation of immnue response and maintenance ofself-tolerance. Studies have found Tregs could suppress tumor-specific T cell-mediated immune response andpromote cancer progression. Depletion of Tregs can enhance antitumor immunity. Dendritic cells (DCs) areprofessional antigen-presenting cells and capable of activating antigen-specific immune responses, which makethem ideal candidate for cancer immunotherapy. Now various DC vaccines are considered as effective treatmentfor cancers. The aim of this study was to evaluate variation of Tregs in BALB/C mice with hepatocellular carcinomaand investigate the interaction between tumor-derived Tregs, effector T cells (Teff) and splenic DCs. We foundthe percentages of Tregs/CD4+ in the peripheral blood of tumor-bearing mice were higher than in normal mice.Tumor-derived Tregs diminished the up-regulation of costimulatory molecule expression on splenic DCs, evenin the presence of Teff cells and simultaneously inhibited IL-12 and TNF-α secretion by DCs. 相似文献
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Although regulatory T cells (Tregs) have been detected in clinically apparent and experimentally induced tumors, the significance of their presence is obscured because past studies examined late-stage tumors that had formed in immunocompetent hosts and thus had evolved mechanisms to escape immunologic recognition and/or elimination. Herein, we report the first comparative analysis of the antitumor response to 3'-methylcholanthrene-induced tumors, which either grow progressively (progressor tumors) or are rejected by the immune system (regressor tumors). Surprisingly, we found that both progressor and regressor tumors harbored proliferating (i.e., activated) Foxp3+CD25+Tregs. However, progressor tumors contained a higher percentage of Tregs in the lymphocyte subset versus regressor tumors. The Tregs in progressor tumors were derived from peripheral CD25+ natural Tregs, accumulated early after tumor challenge and were actively proliferating, suggesting that progressor tumors recruited and/or activated endogenous Tregs as a mechanism of escaping immune destruction. To explore whether Tregs directly contributed to the progressive growth phenotype of progressor tumors, we monitored tumor outgrowth in naive wild-type recipients pretreated with either a control monoclonal antibody (mAb) or a depleting CD25-specific mAb. In mice predepleted of CD25+ cells, the tumors that subsequently developed displayed an increased accumulation of proliferating CD8+ T cells and were rejected. These results show that, although Tregs are activated in both regressor and progressor tumors, the ratio of regulatory to effector T cells is critical in determining whether the host successfully rejects the tumor or eventually succumbs to tumor outgrowth. 相似文献
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目的:观察CD4+CD25+CCR6+调节性T细胞(简称CCR6+Tregs)体内对CD8+T细胞功能的抑制作用,并探讨其与肿瘤免疫逃逸的关系。方法:建立4T1乳腺癌细胞荷瘤裸鼠模型,FACS分选CCR6+Tregs,检测其Foxp3的表达;FACS分选4T1特异性CD8+T细胞,CFSE标记后分别与CCR6+Tregs或CCR6Tregs共同过继转输入4T1荷瘤裸鼠体内,观察荷瘤裸鼠肿瘤生长情况和小鼠存活时间;FACS检测肿瘤组织中CD8+T细胞的增殖、细胞因子IFNγ的产生和颗粒酶B的表达情况。结果:CCR6+Tregs和CCR6Tregs均高表达Foxp3;CCR6+Tregs和CD8+T细胞共转输组4T1荷瘤裸鼠肿瘤的生长明显快于CCR6Tregs共转输组和CD8+T细胞单转输组,同时该组荷瘤裸鼠生存时间也明显缩短(P<0.05);CCR6+Tregs和CD8+T细胞共转输组CD8+T细胞的增殖、IFNγ的产生和颗粒酶B的表达均明显低于CCR6Tregs共转输组和CD8+T细胞单转输组(P<0.05)。结论:CCR6+Tregs在体内可以有效抑制CD8+T细胞的功能,其在肿瘤免疫逃逸和肿瘤发生、发展中发挥重要作用。 相似文献
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Joannes F.M. Jacobs Albert J. Idema Kalijn F. Bol Stefan Nierkens Oliver M. Grauer Pieter Wesseling J. André Grotenhuis Peter M. Hoogerbrugge I. Jolanda M. de Vries Gosse J. Adema 《Neuro-oncology》2009,11(4):394-402
The brain is a specialized immune site representing a unique tumor microenvironment. The availability of fresh brain tumor material for ex vivo analysis is often limited because large parts of many brain tumors are resected using ultrasonic aspiration. We analyzed ultrasonic tumor aspirates as a biosource to study immune suppressive mechanisms in 83 human brain tumors. Lymphocyte infiltrates in brain tumor tissues and ultrasonic aspirates were comparable with respect to lymphocyte content and viability. Applying ultrasonic aspirates, we detected massive infiltration of CD4+FoxP3+CD25high CD127low regulatory T cells (Tregs) in glioblastomas (n = 29) and metastatic brain tumors (n = 20). No Treg accumulation was observed in benign tumors such as meningiomas (n = 10) and pituitary adenomas (n = 5). A significant Treg increase in blood was seen only in patients with metastatic brain tumors. Tregs in high-grade tumors exhibited an activated phenotype as indicated by decreased proliferation and elevated CTLA-4 and FoxP3 expression relative to blood Tregs. Functional analysis showed that the tumor-derived Tregs efficiently suppressed cytokine secretion and proliferation of autologous intratumoral lymphocytes. Most tumor-infiltrating Tregs were localized in close proximity to effector T cells, as visualized by immunohistochemistry. Furthermore, 61% of the malignant brain tumors expressed programmed death ligand-1 (PD-L1), while the inhibitory PD-1 receptor was expressed on CD4+ effector cells present in 26% of tumors. In conclusion, using ultrasonic tumor aspirates as a biosource we identified Tregs and the PD-L1/PD-1 pathway as immune suppressive mechanisms in malignant but not benign human brain tumors. 相似文献
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Masahide Matsuda Keisuke Nimura Takashi Shimbo Toshimitsu Hamasaki Tetsuya Yamamoto Akira Matsumura Yasufumi Kaneda 《Journal of neuro-oncology》2011,103(1):19-31
The hemagglutinating virus of Japan envelope (HVJ-E) vector derived from inactivated replication-defective Sendai virus enhances
anti-tumor immunity through activation of effector T cells and natural killer (NK) cells and inhibition of regulatory T cells
(Tregs). Interleukin (IL)-2 enhances T cell proliferation and activates T cells and NK cells. However, recent studies have
revealed that the application of IL-2 also has immune suppressive effects through expansion of Tregs. Here, we investigated
the efficacy of IL-2 gene therapy using immunomodulating HVJ-E vector in murine malignant glioma models. A single intratumoral
injection of HVJ-E containing pVAX-mIL-2 significantly suppressed tumor growth of intracranial gliomas, resulting in prolonged
survival. Furthermore, HVJ-E, following intracavitary administration, delivered genes into post-operative residual tumor cells.
Consequently, prolonged survival resulted from a single intracavitary administration of HVJ-E containing pVAX-mIL-2 following
tumor removal. IL-2 gene therapy delivered via the HVJ-E vector significantly inhibited the expansion of Tregs in tumors compared
to IL-2 gene transfer using retroviral vector and resulted in marked infiltration of CD4+ and CD8+ T cells into tumors. Through inhibition of Treg-mediated immunosuppression, HVJ-E enhanced effector T cell-mediated anti-tumor
immunity induced by IL-2. This combination of an immunomodulating vector and immunostimulating cytokine gene shows promise
as an attractive, novel immunogene therapy for malignant glioma. 相似文献
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FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis. 总被引:3,自引:0,他引:3
Noritoshi Kobayashi Nobuyoshi Hiraoka Wataru Yamagami Hidenori Ojima Yae Kanai Tomoo Kosuge Atsushi Nakajima Setsuo Hirohashi 《Clinical cancer research》2007,13(3):902-911
PURPOSE: Tumor-infiltrating lymphocytes represent the host immune response to cancer. CD4+CD25+FOXP3+ regulatory T cells (Tregs) suppress the immune reaction. The aim of the present study was to investigate the clinicopathologic significance and roles of Tregs and CD8+ T cells during hepatocarcinogenesis. EXPERIMENTAL DESIGN: We examined the infiltration of FOXP3+ Tregs and CD8+ T cells in the tumor stroma and nontumorous liver parenchyma using 323 hepatic nodules including precursor lesions, early hepatocellular carcinoma (HCC), and advanced HCC, along with 39 intrahepatic cholangiocarcinomas and 59 metastatic liver adenocarcinomas. We did immunohistochemical comparative studies. RESULTS: The prevalence of Tregs was significantly higher in HCC than in the nontumorous liver (P<0.001). The patient group with a high prevalence of Tregs infiltrating HCC showed a significantly lower survival rate (P=0.007). Multivariate analysis revealed that the prevalence of Tregs infiltrating HCC was an independent prognostic factor. The prevalence of Tregs increased in a stepwise manner (P<0.001) and that of CD8+ T cells decreased during the progression of hepatocarcinogenesis (P<0.001). Regardless of the presence of hepatitis virus infection or histopathologic evidence of hepatitis, the prevalence of Tregs was significantly increased in nontumorous liver bearing primary hepatic tumors. CONCLUSIONS: Tregs play a role in controlling the immune response to HCC during the progression of hepatocarcinogenesis. It has been suggested that primary hepatic cancers develop in liver that is immunosuppressed by a marked infiltration of Tregs. A high prevalence of Tregs infiltrating HCC is thought to be an unfavorable prognostic indicator. 相似文献
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IDO和CD4^+CD25^+调节性T细胞在肿瘤免疫逃逸中相互作用的研究进展 总被引:3,自引:0,他引:3
肿瘤可以通过多种方式逃逸机体免疫系统的监控。吲哚胺-2,3双加氧酶(indoleamine.2,3-dioxygenase,IDO)和CD4^+CD25^+调节性T细胞(CD4^+CD25^+ regulatory Tcells,Tregs)是近些年在肿瘤免疫逃逸领域中备受关注的两个重要因素。两者相互作用在肿瘤免疫逃逸机制中起着尤为关键的作用,已引起众多研究者的关注。本文就IDO及Tregs在肿瘤免疫逃逸中的作用以及两者之间的相互关系等方面的研究进展作一综述。 相似文献
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Ramos RN Oliveira CE Gasparoto TH Malaspina TS Belai EB Cavassani KA Garlet GP Silva JS Campanelli AP 《Carcinogenesis》2012,33(4):902-909
Squamous cell carcinoma (SCC) constitutes a microenvironment that could modulate the antitumor immune response. Also, tumor-infiltrating lymphocytes are believed to play complex regulatory roles in antitumor immunity against SCC. The presence of regulatory T cells (Tregs) has been associated with the suppression of tumor-reactive T cells. However, the underlying mechanism for this T cell dysfunction is not clear. We used a multistage model of SCC to examine the role of Treg cells during tumor development. 7,12-dimethylbenz[a]-anthracene/phorbol 12-myristate 13-acetate treatment and systemic depletion of Treg cells using an anti-CD25 monoclonal antibody (PC61) resulted in a decrease in the number and incidence of papilloma. Furthermore, CD25 depletion increased the proportion of CD8(+) and CD4(+) T cells that were isolated from tumor lesions. The levels of interleukin (IL)-1β, IL-10, IL-12, IL-13, interferon-γ, transforming growth factor-β and tumor necrosis factor-α, but not IL-17, were increased in the tumor microenvironment after Treg depletion. Therefore, our results indicated involvement of CD25(+) T cells in SCC development and in the suppression of the inflammatory immune response. 相似文献
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Takashi MaruYama Shuhei Kobayashi Hiroyuki Shibata WanJun Chen Yuji Owada 《Cancer science》2021,112(12):4844-4852
Regulatory T cells (Tregs) in the tumor microenvironment regulate tumor immunity. Programmed cell death protein 1 (PD-1) is known to be expressed on Tregs and plays crucial roles in suppressing tumor immunity. However, the immune checkpoint inhibitor, anti-PD-1 antibody, is known to promote the proliferation of the Treg population in tumor-infiltrating lymphocytes, thereby restricting the efficacy of cancer immunotherapy. In this study, we focused on the curcumin analog GO-Y030, an antitumor chemical. GO-Y030 inhibited the immune-suppressive ability of Tregs via metabolic changes in vitro, even in the presence of immune checkpoint inhibitors. Mechanistically, GO-Y030 inhibited the mTOR-S6 axis in Tregs, which plays a pivotal role in their immune-suppressive ability. GO-Y030 also controlled the metabolism in cultured CD4+ T cells in the presence of TGF-β + IL-6; however, it did not prevent Th17 differentiation. Notably, GO-Y030 significantly inhibited IL-10 production from Th17 cells. In the tumor microenvironment, L-lactate produced by tumors is known to support the suppressive ability of Tregs, and GO-Y030 treatment inhibited L-lactate production via metabolic changes. In addition, experiments in the B16-F10 melanoma mouse model revealed that GO-Y030 helped inhibit the anti-PD-1 immune checkpoint and reduce the Treg population in tumor-infiltrating lymphocytes. Thus, GO-Y030 controls the metabolism of both Tregs and tumors and could serve as a booster for anti-immune checkpoint inhibitors. 相似文献
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Ngar‐Yee Huen Alan Lap‐Yin Pang Jo A. Tucker Tin‐Lap Lee Matteo Vergati Caroline Jochems Chiara Intrivici Vittore Cereda Wai‐Yee Chan Owen M. Rennert Ravi A. Madan James L. Gulley Jeffrey Schlom Kwong Y. Tsang 《International journal of cancer. Journal international du cancer》2013,133(2):373-382
A higher frequency of regulatory T cells (Tregs) has been observed in peripheral blood mononuclear cells (PBMC) of patients with different types of solid tumors and hematological malignancies as compared to healthy donors. In prostate cancer patients, Tregs in PBMC have been shown to have increased suppressive function. Tumor‐induced biological changes in Tregs may enable tumor cells to escape immunosurveillance. We performed genome‐wide expression analyses comparing the expression levels of more than 38,500 genes in Tregs with similar suppressive activity, isolated from the peripheral blood of healthy donors and patients with metastatic castration‐resistant prostate cancer (mCRPC). The differentially expressed genes in mCRPC Tregs are involved in cell cycle processes, cellular growth and proliferation, immune responses, hematological system development and function and the interleukin‐2 (IL‐2) and transforming growth factor‐β (TGF‐β) pathways. Studies revealed that the levels of expression of genes responsible for T‐cell proliferation (C‐FOS, C‐JUN and DUSP1) and cellular migration (RGS1) were greater in Tregs from mCRPC patients as compared to values observed in healthy donors. Increased RGS1 expression in Tregs from mCRPC patients suggests a decrease in these Tregs' migratory ability. In addition, the higher frequency of CD4+CD25highCD127– Tregs in the peripheral blood of mCRPC patients may be the result of an increase in Treg proliferation capacity. Results also suggest that the alterations observed in gene expression profiles of Tregs in mCRPC patients may be part of the mechanism of tumor escape from host immune surveillance. 相似文献
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《Asian Pacific journal of cancer prevention》2012,13(8):3815-3819
The CD4+CD25+ regulatory T cell (Treg) is a special kind of T cell subset. Studies have showed that Tregcells are involved in a number of physiological processes and pathologic conditions such as autoimmune diseases,transplantation tolerance and cancer. Tregs with unique capacity for immune inhibition can impair anti-tumourimmunity and help tumor cells to escape from immune surveillance. The aim of our study was to investigatewhether Tregs are involved in hepatocellular carcinoma (HCC). A BABL/C mouse with HCC in situ model wasestablished to evaluate the Treg existence in carcinoma tissues and the changes of Tregs in spleen using flowcytometry and immunohistochemistry methods. Granzyme B expression in carcinoma tissues was analyzedby immunohistochemistry to investigate the tumor local immune status.The proportion of CD4+CD25+/CD4+spleen lymphocytes of tumor bearing mice (18.8%±1.26%) was found to be significantly higher than that innormal mice (9.99%±1.90%) (P<0.01 ). Immunohistochemistry of spleen tissue also confirmed that there wasan increase in Treg in tumor-bearing mice, while in carcinomas it showed Treg cells to be present in tumorinfiltrating lymphocyte areas while Granzyme B was rarely observed. Anti-tumour immunity was suppressed,and this might be associated with the increase of Tregs. Our observations suggest that the CD4+CD25+Treg/CD4+ proportion in spleen lymphocytes can be a sensitive index to evaluate the change of Tregs in hepatocellularcarcinoma mice and the Treg may be a promising therapeutic target for cancer. 相似文献
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Emily J. Colbeck James P. Hindley Kathryn Smart Emma Jones Anja Bloom Hayley Bridgeman Rhoanne C. McPherson Darryl G. Turner Kristin Ladell David A. Price Richard A. O'Connor Stephen M. Anderton Andrew J. Godkin Awen M. Gallimore 《Oncotarget》2015,6(28):24649-24659
Foxp3+ regulatory T cells (Tregs) are often highly enriched within the tumor-infiltrating T cell pool. Using a well-characterised model of carcinogen-induced fibrosarcomas we show that the enriched tumor-infiltrating Treg population comprises largely of CXCR3+ T-bet+ ‘TH1-like’ Tregs which are thymus-derived Helios+ cells. Whilst IL-2 maintains homeostatic ratios of Tregs in lymphoid organs, we found that the perturbation in Treg frequencies in tumors is IL-2 independent. Moreover, we show that the TH1 phenotype of tumor-infiltrating Tregs is dispensable for their ability to influence tumor progression. We did however find that unlike Tconvs, the majority of intra-tumoral Tregs express the activation markers CD69, CD25, ICOS, CD103 and CTLA4 and are significantly more proliferative than Tconvs. Moreover, we have found that CD69+ Tregs are more suppressive than their CD69− counterparts. Collectively, these data indicate superior activation of Tregs in the tumor microenvironment, promoting their suppressive ability and selective proliferation at this site. 相似文献