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山东大学学报 (医学版) ›› 2020, Vol. 58 ›› Issue (8): 67-73.doi: 10.6040/j.issn.1671-7554.0.2020.430

• 脑科学与类脑智能研究专题 • 上一篇    下一篇

脑胶质瘤抑制性免疫微环境形成机制及研究进展

李刚*(),薛皓,邱伟,赵荣荣   

  1. 山东大学齐鲁医院神经外科，山东 济南 250012
  • 收稿日期:2020-03-24 出版日期:2020-08-01 发布日期:2020-08-07
  • 通讯作者: 李刚 E-mail:dr.ligang@sdu.edu.cn
  • 作者简介:李刚，医学博士，主任医师，山东大学特聘教授及二级岗专家，博士研究生导师，泰山学者特聘专家；现任山东大学齐鲁医院神经外科主任，山东大学脑与类脑科学研究院副院长；兼任山东省医学会神经外科分会主任委员，中华医学会神经外科分会委员及脑血管病外科学组副组长，中国医师协会神经外科医师分会常务委员及脑胶质瘤专业委员会副主任委员；同时担任《中华神经外科杂志》《中华神经外科杂志(英文)》《Neurosurgery》中文版等多家期刊的编委|主要研究方向为胶质瘤抑制性免疫微环境形成机制、胶质瘤标志物与胶质瘤早期精准诊疗；先后承担国家自然科学基金面上项目5项、国家自然科学基金重大培育项目1项、国家“十二五”重大科技支撑计划子课题2项、省部级课题10余项；获山东省科技进步一等奖2项、教育部科技进步二等奖1项、中华医学科技三等奖1项、山东省科技进步二等奖4项及山东省高校优秀科技成果一等奖2项；授权国家发明专利6项、实用新型专利5项；以第一或通讯作者在《Autophagy》《J Pineal Res》《Oncogene》《Brain Pathol》《Int J Cancer》等著名学术期刊发表SCI收录论文80余篇；主编、副主编及参编著作10余部
  • 基金资助:
    国家自然科学基金(81874083);山东省重点研发计划(2017CXGC1203);泰山学者基金(ts201511093)

Research advances in the formation of glioma immunosuppressive microenvironment

Gang LI*(),Hao XUE,Wei QIU,Rongrong ZHAO   

  1. Department of Neurosurgery, Qilu Hospital, Cheeloo College of Meicine, Shandong University, Jinan 250012, Shandong, China
  • Received:2020-03-24 Online:2020-08-01 Published:2020-08-07
  • Contact: Gang LI E-mail:dr.ligang@sdu.edu.cn

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摘要：

人脑胶质瘤是中枢神经系统最常见的恶性肿瘤，手术切除及放化疗等传统治疗方法效果不理想。近年来，多种免疫治疗策略相继问世，然而由于胶质瘤抑制性免疫微环境的存在，上述疗法仍不尽如人意。探究胶质瘤抑制性免疫微环境的形成机制，是胶质瘤免疫治疗亟需解决的问题。本文结合相关研究领域最新研究进展，对胶质瘤抑制性微环境的研究方向进行总结及展望，为系统全面了解胶质瘤免疫微环境提供重要参考。

关键词: 胶质瘤, 抑制性免疫微环境, 免疫治疗

Abstract:

As the most common and lethal primary tumor of the central nervous system, glioma responds poorly to conventional treatments. Although novel immunotherapies have been adopted, the prognosis of glioma patients is still poor due to the immunosuppressive microenvironment. Therefore, a thorough investigation of the formation mechanism of glioma immunosuppressive microenvironment has become the focus. Based on the latest research progress, we summarized and prospected the future research direction of glioma immunosuppressive microenvironment, hoping to provide reference for the better understanding of this disease.

Key words: Glioma, Immunosuppressive microenvironment, Immunotherapy

中图分类号: 

  • R739.41
1 Savage N . Searching for the roots of brain cancer[J]. Nature, 2018, 561 (7724): S50- S51.
doi: 10.1038/d41586-018-06709-2
2 June CH , O'Connor RS , Kawalekar OU , et al. CAR T cell immunotherapy for human cancer[J]. Science, 2018, 359 (6382): 1361- 1365.
doi: 10.1126/science.aar6711
3 Voorwerk L , Slagter M , Horlings HM , et al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial[J]. Nat Med, 2019, 25 (6): 920- 928.
doi: 10.1038/s41591-019-0432-4
4 Garner H , de Visser KE . Immune crosstalk in cancer progression and metastatic spread: a complex conversation[J]. Nat Rev Immunol, 2020, 20 (8): 483- 497.
doi: 10.1038/s41577-019-0271-z
5 Galon J , Bruni D . Tumor immunology and tumor evolution: intertwined histories[J]. Immunity, 2020, 52 (1): 55- 81.
doi: 10.1016/j.immuni.2019.12.018
6 Quail DF , Joyce JA . The microenvironmental landscape of brain tumors[J]. Cancer Cell, 2017, 31 (3): 326- 341.
doi: 10.1016/j.ccell.2017.02.009
7 Xie F , Zhou X , Fang M , et al. Extracellular vesicles in cancer immune microenvironment and cancer immunotherapy[J]. Adv Sci (Weinh), 2019, 6 (24): 1901779.
doi: 10.1002/advs.201901779
8 Cheng J , Meng J , Zhu L , et al. Exosomal noncoding RNAs in Glioma: biological functions and potential clinical applications[J]. Mol Cancer, 2020, 19 (1): 66.
doi: 10.1186/s12943-020-01189-3
9 Qian M , Wang S , Guo X , et al. Hypoxic glioma-derived exosomes deliver microRNA-1246 to induce M2 macrophage polarization by targeting TERF2IP via the STAT3 and NF-kappaB pathways[J]. Oncogene, 2020, 39 (2): 428- 442.
doi: 10.1038/s41388-019-0996-y
10 Guo X , Qiu W , Liu Q , et al. Immunosuppressive effects of hypoxia-induced glioma exosomes through myeloid-derived suppressor cells via the miR-10a/Rora and miR-21/Pten Pathways[J]. Oncogene, 2018, 37 (31): 4239- 4259.
doi: 10.1038/s41388-018-0261-9
11 Guo X , Qiu W , Wang J , et al. Glioma exosomes mediate the expansion and function of myeloid-derived suppressor cells through microRNA-29a/Hbp1 and microRNA-92a/Prkar1a pathways[J]. Int J Cancer, 2019, 144 (12): 3111- 3126.
doi: 10.1002/ijc.32052
12 Arvanitis CD , Ferraro GB , Jain RK . The blood-brain barrier and blood-tumour barrier in brain tumours and metastases[J]. Nat Rev Cancer, 2020, 20 (1): 26- 41.
doi: 10.1038/s41568-019-0205-x
13 Prinz M , Priller J , Sisodia SS , et al. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration[J]. Nat Neurosci, 2011, 14 (10): 1227- 1235.
doi: 10.1038/nn.2923
14 Kettenmann H , Hanisch UK , Noda M , et al. Physiology of microglia[J]. Physiol Rev, 2011, 91 (2): 461- 553.
15 Gutmann DH , Kettenmann H . Microglia/brain macrophages as central drivers of brain tumor pathobiology[J]. Neuron, 2019, 104 (3): 442- 449.
doi: 10.1016/j.neuron.2019.08.028
16 Norris GT , Kipnis J . Immune cells and CNS physiology: microglia and beyond[J]. J Exp Med, 2019, 216 (1): 60- 70.
doi: 10.1084/jem.20180199
17 Poon CC , Sarkar S , Yong VW , et al. Glioblastoma-associated microglia and macrophages: targets for therapies to improve prognosis[J]. Brain, 2017, 140 (6): 1548- 1560.
doi: 10.1093/brain/aww355
18 Wei J , Chen P , Gupta P , et al. Immune biology of glioma-associated macrophages and microglia: functional and therapeutic implications[J]. Neuro Oncol, 2020, 22 (2): 180- 194.
19 Wright-Jin EC , Gutmann DH . Microglia as dynamic cellular mediators of brain function[J]. Trends Mol Med, 2019, 25 (11): 967- 979.
doi: 10.1016/j.molmed.2019.08.013
20 Chen P , Hsu WH , Chang A , et al. Circadian regulator CLOCK recruits immune-suppressive microglia into the GBM tumor microenvironment[J]. Cancer Discov, 2020, 10 (3): 371- 381.
doi: 10.1158/2159-8290.CD-19-0400
21 Abels ER , Maas SLN , Nieland L , et al. Glioblastoma-associated microglia reprogramming is mediated by functional transfer of extracellular miR-21[J]. Cell Rep, 2019, 28 (12): 3105- 3119.
doi: 10.1016/j.celrep.2019.08.036
22 Yu-Ju Wu C , Chen CH , Lin CY , et al. CCL5 of glioma-associated microglia/macrophages regulates glioma migration and invasion via calcium-dependent matrix metalloproteinase 2[J]. Neuro Oncol, 2020, 22 (2): 253- 266.
doi: 10.1093/neuonc/noz189
23 Qian J , Luo F , Yang J , et al. TLR2 promotes glioma immune evasion by downregulating MHC class II molecules in microglia[J]. Cancer Immunol Res, 2018, 6 (10): 1220- 1233.
24 Guo X , Xue H , Shao Q , et al. Hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR[J]. Oncotarget, 2016, 7 (49): 80521- 80542.
doi: 10.18632/oncotarget.11825
25 Zong CC . Single-cell RNA-seq study determines the ontogeny of macrophages in glioblastomas[J]. Genome Biol, 2017, 18 (1): 235.
doi: 10.1186/s13059-017-1375-z
26 Yan D , Kowal J , Akkari L , et al. Inhibition of colony stimulating factor-1 receptor abrogates microenvironment-mediated therapeutic resistance in gliomas[J]. Oncogene, 2017, 36 (43): 6049- 6058.
doi: 10.1038/onc.2017.261
27 Sylvestre M , Crane CA , Pun SH . Progress on modulating tumor-associated macrophages with biomaterials[J]. Adv Mater, 2020, 32 (13): e1902007.
doi: 10.1002/adma.201902007
28 Vetsika EK , Koukos A , Kotsakis A . Myeloid-derived suppressor cells: major figures that shape the immunosuppressive and angiogenic network in cancer[J]. Cells, 2019, 8 (12): 1647.
doi: 10.3390/cells8121647
29 Kumar V , Patel S , Tcyganov E , et al. The nature of myeloid-derived suppressor cells in the tumor microenvironment[J]. Trends Immunol, 2016, 37 (3): 208- 220.
doi: 10.1016/j.it.2016.01.004
30 Waziri A . Glioblastoma-derived mechanisms of systemic immunosuppression[J]. Neurosurg Clin N Am, 2010, 21 (1): 31- 42.
doi: 10.1016/j.nec.2009.08.005
31 Chae M , Peterson TE , Balgeman A , et al. Increasing glioma-associated monocytes leads to increased intratumoral and systemic myeloid-derived suppressor cells in a murine model[J]. Neuro Oncol, 2015, 17 (7): 978- 991.
doi: 10.1093/neuonc/nou343
32 Chang AL , Miska J , Wainwright DA , et al. CCL2 Produced by the glioma microenvironment is essential for the recruitment of regulatory T cells and myeloid-derived suppressor cells[J]. Cancer Res, 2016, 76 (19): 5671- 5682.
doi: 10.1158/0008-5472.CAN-16-0144
33 Flores-Toro JA , Luo D , Gopinath A , et al. CCR2 inhibition reduces tumor myeloid cells and unmasks a checkpoint inhibitor effect to slow progression of resistant murine gliomas[J]. Proc Natl Acad Sci U S A, 2020, 117 (2): 1129- 1138.
doi: 10.1073/pnas.1910856117
34 Le Gall CM , Weiden J , Eggermont LJ , et al. Dendritic cells in cancer immunotherapy[J]. Nat Mater, 2018, 17 (6): 474- 475.
doi: 10.1038/s41563-018-0093-6
35 Yan J , Zhao Q , Gabrusiewicz K , et al. FGL2 promotes tumor progression in the CNS by suppressing CD103(+) dendritic cell differentiation[J]. Nat Commun, 2019, 10 (1): 448.
doi: 10.1038/s41467-018-08271-x
36 刘鸿宇, 沈少平, 杨霖, 等. 树突状细胞疫苗在恶性胶质瘤免疫治疗中的应用[J]. 中国现代神经疾病杂志, 2020, 20 (2): 119- 126.
LIU Hongyu , SHEN Shaoping , YANG Lin , et al. The application of dendritic cells vaccination in malignant glioma[J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2020, 20 (2): 119- 126.
37 Nicolas-Avila JA , Adrover JM , Hidalgo A . Neutrophils in homeostasis, immunity, and cancer[J]. Immunity, 2017, 46 (1): 15- 28.
doi: 10.1016/j.immuni.2016.12.012
38 Bertaut A , Truntzer C , Madkouri R , et al. Blood baseline neutrophil count predicts bevacizumab efficacy in glioblastoma[J]. Oncotarget, 2016, 7 (43): 70948- 70958.
doi: 10.18632/oncotarget.10898
39 Liang J , Piao Y , Holmes L , et al. Neutrophils promote the malignant glioma phenotype through S100A4[J]. Clin Cancer Res, 2014, 20 (1): 187- 198.
doi: 10.1158/1078-0432.CCR-13-1279
40 Khan S , Mittal S , McGee K , et al. Role of neutrophils and myeloid-derived suppressor cells in glioma progression and treatment resistance[J]. Int J Mol Sci, 2020, 21 (6): 1954.
doi: 10.3390/ijms21061954
41 Shaul ME , Fridlender ZG . Cancer-related circulating and tumor-associated neutrophils-subtypes, sources and function[J]. FEBS J, 2018, 285 (23): 4316- 4342.
doi: 10.1111/febs.14524
42 van der Leun AM , Thommen DS , Schumacher TN . CD8(+) T cell states in human cancer: insights from single-cell analysis[J]. Nat Rev Cancer, 2020, 20 (4): 218- 232.
doi: 10.1038/s41568-019-0235-4
43 Sharonov GV , Serebrovskaya EO , Yuzhakova DV , et al. B cells, plasma cells and antibody repertoires in the tumour microenvironment[J]. Nat Rev Immunol, 2020, 20 (5): 294- 307.
doi: 10.1038/s41577-019-0257-x
44 Miska J , Lee-Chang C , Rashidi A , et al. HIF-1alpha is ametabolic switch between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression of tregs in glioblastoma[J]. Cell Rep, 2019, 27 (1): 226- 237.
45 Togashi Y , Shitara K , Nishikawa H . Regulatory T cells in cancer immunosuppression-implications for anticancer therapy[J]. Nat Rev Clin Oncol, 2019, 16 (6): 356- 371.
doi: 10.1038/s41571-019-0175-7
46 Nehama D , Di Ianni N , Musio S , et al. B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres[J]. EBioMedicine, 2019, 47: 33- 43.
doi: 10.1016/j.ebiom.2019.08.030
47 Choi BD , Yu X , Castano AP , et al. CRISPR-Cas9 disruption of PD-1 enhances activity of universal EGFRvIII CAR T cells in a preclinical model of human glioblastoma[J]. J Immunother Cancer, 2019, 7 (1): 304.
48 Figueroa J , Phillips LM , Shahar T , et al. Exosomes from glioma-associated mesenchymal stem cells increase the tumorigenicity of glioma stem-like cells via transfer of miR-1587[J]. Cancer Res, 2017, 77 (21): 5808- 5819.
doi: 10.1158/0008-5472.CAN-16-2524
49 Shahar T , Rozovski U , Hess KR , et al. Percentage of mesenchymal stem cells in high-grade glioma tumor samples correlates with patient survival[J]. Neuro Oncol, 2017, 19 (5): 660- 668.
50 Tumangelova-Yuzeir K , Naydenov E , Ivanova-Todorova E , et al. Mesenchymal stem cells derived and cultured from glioblastoma multiforme increase tregs, downregulate Th17, and induce the tolerogenic phenotype of monocyte-derived cells[J]. Stem Cells Int, 2019, 2019: 6904638.
doi: 10.1155/2019/6904638.eCollection2019
51 Cloughesy TF , Mochizuki AY , Orpilla JR , et al. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma[J]. Nat Med, 2019, 25 (3): 477- 486.
doi: 10.1038/s41591-018-0337-7
52 Schalper KA , Rodriguez-Ruiz ME , Diez-Valle R , et al. Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma[J]. Nat Med, 2019, 25 (3): 470- 476.
doi: 10.1038/s41591-018-0339-5
53 Zhao J , Chen AX , Gartrell RD , et al. Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma[J]. Nat Med, 2019, 25 (3): 462- 469.
doi: 10.1038/s41591-019-0349-y
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