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中华乳腺病杂志(电子版) ›› 2018, Vol. 12 ›› Issue (03) : 165 -171. doi: 10.3877/cma.j.issn.1674-0807.2018.03.008

所属专题: 文献

综述

乳腺肿瘤免疫微环境及其在临床免疫治疗中的应用
谭璐媛1, 王妍1, 钟文静1, 龚畅1,()   
  1. 1. 510120 广州,中山大学孙逸仙纪念医院乳腺肿瘤中心
  • 收稿日期:2017-09-19 出版日期:2018-06-01
  • 通信作者: 龚畅
  • 基金资助:
    国家科技部重点研发计划资助项目(2017YFC1309100); 国家自然科学基金资助项目(81472466、81672594、81772836); 广东省自然科学基金资助项目(2014A03036003、2016A050502018); 中山大学培育计划资助项目(17ykjc13)

Immune microenvironment in breast tumor and its application in clinical immunotherapy

Luyuan Tan1, Yan Wang1, Wenjing Zhong1   

  • Received:2017-09-19 Published:2018-06-01
引用本文:

谭璐媛, 王妍, 钟文静, 龚畅. 乳腺肿瘤免疫微环境及其在临床免疫治疗中的应用[J]. 中华乳腺病杂志(电子版), 2018, 12(03): 165-171.

Luyuan Tan, Yan Wang, Wenjing Zhong. Immune microenvironment in breast tumor and its application in clinical immunotherapy[J]. Chinese Journal of Breast Disease(Electronic Edition), 2018, 12(03): 165-171.

免疫微环境中存在不同激活状态的免疫细胞。不同分子表型的乳腺肿瘤中免疫细胞浸润程度不同,其免疫细胞的数量和状态可作为预测乳腺肿瘤患者预后和疗效的重要指标。因此,研究免疫细胞之间及其与肿瘤细胞之间的相互作用机制以及免疫细胞作为诊断标志物和治疗靶点的临床应用价值,是当今肿瘤领域的热点。笔者总结了肿瘤免疫微环境在乳腺肿瘤发生、发展中的作用及其作为免疫治疗靶点的临床应用潜能。

[1]
Ajani JA, Song S, Hochster HS, et al. Cancer stem cells: the promise and the potential[J]. Semin Oncol, 2015, 42 Suppl 1: S3-17.
[2]
Verma M, Rogers S, Divi RL, et al. Epigenetic research in cancer epidemiology: trends, opportunities, and challenges[J]. Cancer Epidemiol Biomarkers Prev, 2014, 23(2): 223-233.
[3]
Kane JR, Miska J, Young JS, et al. Sui generis: gene therapy and delivery systems for the treatment of glioblastoma[J]. Neuro Oncol, 2015, 17 Suppl 2: ii24-ii36.
[4]
Baader E, Toloczko A, Fuchs U, et al. Tumor necrosis factor-related apoptosis-inducing ligand-mediated proliferation of tumor cells with receptor-proximal apoptosis defects[J]. Cancer Res, 2005, 65(17): 7888-7895.
[5]
Hui L, Chen Y. Tumor microenvironment: Sanctuary of the devil[J]. Cancer Lett, 2015, 368(1): 7-13.
[6]
Paget S. The distribution of secondary growths in cancer of the breast. 1889[J]. Cancer Metastasis Rev, 1989, 8(2): 98-101.
[7]
Hoshino A, Costa-Silva B, Shen TL, et al. Tumour exosome integrins determine organotropic metastasis[J]. Nature, 2015, 527(7578): 329-335.
[8]
Mumm JB, Emmerich J, Zhang X, et al. IL-10 elicits IFN gamma-dependent tumor immune surveillance[J]. Cancer Cell, 2011, 20(6): 781-796.
[9]
Heinrich EL, Walser TC, Krysan K, et al. The inflammatory tumor microenvironment, epithelial mesenchymal transition and lung carcinogenesis[J]. Cancer Microenviron, 2012, 5(1): 5-18.
[10]
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation[J]. Cell, 2011, 144(5): 646-674.
[11]
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy[J]. Nat Rev Cancer, 2012, 12(4): 252-264.
[12]
Beatty GL, Gladney WL. Immune escape mechanisms as a guide for cancer immunotherapy[J]. Clin Cancer Res, 2015, 21(4): 687-692.
[13]
Ruffell B, Au A, Rugo HS, et al. Leukocyte composition of human breast cancer[J]. Proc Natl Acad Sci U S A, 2012, 109(8): 2796-2801.
[14]
Gregory AD, Houghton AM. Tumor-associated neutrophils: new targets for cancer therapy[J]. Cancer Res, 2011, 71(7): 2411-2416.
[15]
Denkert C, Loibl S, Noske A, et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer[J]. J Clin Oncol, 2010, 28(1): 105-113.
[16]
Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations [J]. Annu Rev Immunol, 2010, 28: 445-489.
[17]
Chen J, Yao Y, Gong C, et al. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3[J]. Cancer Cell, 2011, 19(4): 541-555.
[18]
Gaur P, Singh AK, Shukla NK, et al. Inter-relation of Th1, Th2, Th17 and Treg cytokines in oral cancer patients and their clinical significance[J]. Hum Immunol, 2014, 75(4): 330-337.
[19]
Martin F, Apetoh L, Ghiringhelli F. Controversies on the role of Th17 in cancer: a TGF-β-dependent immunosuppressive activity?[J]. Trends Mol Med, 2012, 18(12): 742-749.
[20]
Yang L, Qi Y, Hu J, et al. Expression of Th17 cells in breast cancer tissue and its association with clinical parameters[J]. Cell Biochem Biophys, 2012, 62(1): 153-159.
[21]
Kato M, Oiso N, Itoh T, et al. Necrobiosis lipoidica with infiltration of Th17 cells into vascular lesions[J]. J Dermatol, 2014, 41(5): 459-461.
[22]
Liu S, Lachapelle J, Leung S, et al. CD8+ lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer[J]. Breast Cancer Res, 2012, 14(2): R48.
[23]
Mahmoud SM, Paish EC, Powe DG, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer[J]. J Clin Oncol, 2011, 29(15): 1949-1955.
[24]
Ali HR, Provenzano E, Dawson SJ, et al. Association between CD8+ T-cell infiltration and breast cancer survival in 12, 439 patients[J]. Ann Oncol, 2014, 25(8): 1536-1543.
[25]
Curtis C, Shah SP, Chin SF, et al. The genomic and transcriptomic architecture of 2, 000 breast tumours reveals novel subgroups[J]. Nature, 2012, 486(7403): 346-352.
[26]
Liu S, Foulkes WD, Leung S, et al. Prognostic significance of FOXP3+ tumor-infiltrating lymphocytes in breast cancer depends on estrogen receptor and human epidermal growth factor receptor-2 expression status and concurrent cytotoxic T-cell infiltration[J]. Breast Cancer Res, 2014, 16(5): 432.
[27]
Shin JI, Ha SJ. Regulatory T cells-an important target for cancer immunotherapy[J]. Nat Rev Clin Oncol, 2014, 11(6): 307.
[28]
Su S, Liao J, Liu J, et al. Blocking the recruitment of naive CD4+ T cells reverses immunosuppression in breast cancer[J]. Cell Res, 2017, 27(4): 461-482.
[29]
Nelson BH. CD20+ B cells: the other tumor-infiltrating lymphocytes[J]. J Immunol, 2010, 185(9): 4977-4982.
[30]
Schmidt M, Bohm D, von Torne C, et al. The humoral immune system has a key prognostic impact in node-negative breast cancer[J]. Cancer Res, 2008, 68(13): 5405-5413.
[31]
Kotlan B, Simsa P, Teillaud JL, et al. Novel ganglioside antigen identified by B cells in human medullary breast carcinomas: the proof of principle concerning the tumor-infiltrating B lymphocytes[J]. J Immunol, 2005, 175(4): 2278-2285.
[32]
Carmi Y, Spitzer MH, Linde IL, et al. Allogeneic IgG combined with dendritic cell stimuli induce antitumour T-cell immunity[J]. Nature, 2015, 521(7550): 99-104.
[33]
Olkhanud PB, Damdinsuren B, Bodogai M, et al. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4(+) T cells to T-regulatory cells[J]. Cancer Res, 2011, 71(10): 3505-3515.
[34]
Tang X. Tumor-associated macrophages as potential diagnostic and prognostic biomarkers in breast cancer[J]. Cancer Lett, 2013, 332(1): 3-10.
[35]
Hollmen M, Roudnicky F, Karaman S, et al. Characterization of macrophage--cancer cell crosstalk in estrogen receptor positive and triple-negative breast cancer[J]. Sci Rep, 2015, 5: 9188.
[36]
Radvanyi L, Pilon-Thomas S, Peng W, et al. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer--letter[J]. Clin Cancer Res, 2013, 19(19): 5541.
[37]
Fridlender ZG, Sun J, Kim S, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: " N1" versus " N2" TAN[J]. Cancer Cell, 2009, 16(3): 183-194.
[38]
Droeser R, Zlobec I, Kilic E, et al. Differential pattern and prognostic significance of CD4+, FOXP3+ and IL-17+ tumor infiltrating lymphocytes in ductal and lobular breast cancers[J]. BMC Cancer, 2012, 12: 134.
[39]
Gu-Trantien C, Loi S, Garaud S, et al. CD4(+) follicular helper T cell infiltration predicts breast cancer survival[J]. J Clin Invest, 2013, 123(7): 2873-2892.
[40]
Su S, Liao J, Liu J, et al.Blocking the recruitment of naive CD4+ T cells reverses immunosuppression in breast cancer[J]. Cell Res, 2017, 27(4): 461-482.
[41]
Mahmoud SM, Paish EC, Powe DG, et al. An evaluation of the clinical significance of FOXP3+ infiltrating cells in human breast cancer[J]. Breast Cancer Res Treat, 2011, 127(1): 99-108.
[42]
West NR, Kost SE, Martin SD, et al. Tumour-infiltrating FOXP3(+) lymphocytes are associated with cytotoxic immune responses and good clinical outcome in oestrogen receptor-negative breast cancer[J]. Br J Cancer, 2013, 108(1): 155-162.
[43]
Mohammed ZM, Going JJ, Edwards J, et al. The relationship between lymphocyte subsets and clinico-pathological determinants of survival in patients with primary operable invasive ductal breast cancer[J]. Br J Cancer, 2013, 109(6): 1676-1684.
[44]
Mahmoud SM, Lee AH, Paish EC, et al. The prognostic significance of B lymphocytes in invasive carcinoma of the breast[J]. Breast Cancer Res Treat, 2012, 132(2): 545-553.
[45]
Iglesia MD, Vincent BG, Parker JS, et al. Prognostic B-cell signatures using mRNA-seq in patients with subtype-specific breast and ovarian cancer[J]. Clin Cancer Res, 2014, 20(14): 3818-3829.
[46]
Ascierto ML, Kmieciak M, Idowu MO, et al. A signature of immune function genes associated with recurrence-free survival in breast cancer patients[J]. Breast Cancer Res Treat, 2012, 131(3): 871-880.
[47]
Medrek C, Ponten F, Jirstrom K, et al. The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients[J]. BMC Cancer, 2012, 12: 306.
[48]
Mahmoud SM, Lee AH, Paish EC, et al. Tumour-infiltrating macrophages and clinical outcome in breast cancer[J]. J Clin Pathol, 2012, 65(2): 159-163.
[49]
Tiainen S, Tumelius R, Rilla K, et al. High numbers of macrophages, especially M2-like (CD163-positive), correlate with hyaluronan accumulation and poor outcome in breast cancer[J]. Histopathology, 2015, 66(6): 873-883.
[50]
Su S, Liu Q, Chen J, et al. A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis[J]. Cancer Cell, 2014, 25(5): 605-620.
[51]
Huang D, Song SJ, Wu ZZ, et al. Epstein-barr virus-induced VEGF and GM-CSF drive nasopharyngeal carcinoma metastasis via recruitment and activation of macrophages[J]. Cancer Res, 2017, 77(13): 3591-3604.
[52]
Soto-Perez-de-Celis E, Chavarri-Guerra Y, Leon-Rodriguez E, et al. Tumor-associated neutrophils in breast cancer subtypes[J]. Asian Pac J Cancer Prev, 2017, 18(10): 2689-2693.
[53]
Carus A, Ladekarl M, Hager H, et al. Tumour-associated CD66b+ neutrophil count is an independent prognostic factor for recurrence in localised cervical cancer[J]. Br J Cancer, 2013, 108(10): 2116-2122.
[54]
Vincent J, Mignot G, Chalmin F, et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity[J]. Cancer Res, 2010, 70(8): 3052-3061.
[55]
Chafe SC, Lou Y, Sceneay J, et al. Carbonic anhydrase IX promotes myeloid-derived suppressor cell mobilization and establishment of a metastatic niche by stimulating G-CSF production[J]. Cancer Res, 2015, 75(6): 996-1008.
[56]
Yu J, Du W, Yan F, et al. Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer[J]. J Immunol, 2013, 190(7): 3783-3797.
[57]
Markowitz J, Wesolowski R, Papenfuss T, et al. Myeloid-derived suppressor cells in breast cancer[J]. Breast Cancer Res Treat, 2013, 140(1): 13-21.
[58]
Lee HJ, Lee JJ, Song IH, et al. Prognostic and predictive value of NanoString-based immune-related gene signatures in a neoadjuvant setting of triple-negative breast cancer: relationship to tumor-infiltrating lymphocytes[J]. Breast Cancer Res Treat, 2015, 151(3): 619-627.
[59]
Loi S, Sirtaine N, Piette F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98[J]. J Clin Oncol, 2013, 31(7): 860-867.
[60]
Oda N, Shimazu K, Naoi Y, et al. Intratumoral regulatory T cells as an independent predictive factor for pathological complete response to neoadjuvant paclitaxel followed by 5-FU/epirubicin/cyclophosphamide in breast cancer patients[J]. Breast Cancer Res Treat, 2012, 136(1): 107-116.
[61]
Chen Y, Chen K, Xiao X, et al. Pretreatment neutrophil-to-lymphocyte ratio is correlated with response to neoadjuvant chemotherapy as an independent prognostic indicator in breast cancer patients: a retrospective study[J]. BMC Cancer, 2016, 16: 320.
[62]
Perez EA, Thompson EA, Ballman KV, et al. Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group n9831 Adjuvant Trastuzumab Trial[J]. J Clin Oncol, 2015, 33(7): 701-708.
[63]
Sliwkowski MX, Lofgren JA, Lewis GD, et al. Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin)[J]. Semin Oncol, 1999, 26(4 Suppl 12): 60-70.
[64]
Hudis CA. Trastuzumab-mechanism of action and use in clinical practice[J].N Engl J Med, 2007, 357(1): 39-51.
[65]
Bianchini G, Gianni L. The immune system and response to HER2-targeted treatment in breast cancer[J]. Lancet Oncol, 2014, 15(2): e58-68.
[66]
Gennari R, Menard S, Fagnoni F, et al. Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2[J]. Clin Cancer Res, 2004, 10(17): 5650-5655.
[67]
Nguyen LT, Ohashi PS. Clinical blockade of PD1 and LAG3--potential mechanisms of action[J]. Nat Rev Immunol, 2015, 15(1): 45-56.
[68]
Muenst S, Soysal SD, Gao F, et al. The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer[J]. Breast Cancer Res Treat, 2013, 139(3): 667-676.
[69]
Nanda R, Chow LQ, Dees EC, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study[J]. J Clin Oncol, 2016, 34(21): 2460-2467.
[70]
Early Breast Cancer Trialists’Collaborative Group. Effects of radiotherapy and surgery in early breast cancer. An overview of the randomized trials. [J]. N Engl J Med, 1995, 333(22): 1444-1455.
[71]
Burugu S, Asleh-Aburayaand K, Nielsen TO. Immune infiltrates in the breast cancer microenvironment: detection, characterization and clinical implication[J]. Breast Cancer, 2017, 24(1): 3-15.
[72]
Vonderheide RH, LoRusso PM, Khalil M, et al. Tremelimumab in combination with exemestane in patients with advanced breast cancer and treatment-associated modulation of inducible costimulator expression on patient T cells[J]. Clin Cancer Res, 2010, 16(13): 3485-3494.
[73]
Keogh E, Fikes J, Southwood S, et al. Identification of new epitopes from four different tumor-associated antigens: recognition of naturally processed epitopes correlates with HLA-A*0201-binding affinity[J]. J Immunol, 2001, 167(2): 787-796.
[74]
Peoples GE, Gurney JM, Hueman MT, et al. Clinical trial results of a HER2/neu (E75) vaccine to prevent recurrence in high-risk breast cancer patients[J]. J Clin Oncol, 2005, 23(30): 7536-7545.
[75]
Mittendorf EA, Ardavanis A, Litton JK, et al. Primary analysis of a prospective, randomized, single-blinded phase II trial evaluating the HER2 peptide GP2 vaccine in breast cancer patients to prevent recurrence[J]. Oncotarget, 2016, 7(40): 66 192-66 201.
[76]
Brentjens RJ, Riviere I, Park JH, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias[J]. Blood, 2011, 118(18): 4817-4828.
[77]
Carpenito C, Milone MC, Hassan R, et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains[J]. Proc Natl Acad Sci, 2009, 106(9): 3360-3365.
[78]
Zhao Y, Wang QJ. A herceptin-based chimeric antigen receptor with modified signaling domains leads to enhanced survival of transduced T lymphocytes and antitumor activity[J]. J Immunol, 2009, 183(9): 5563-5574.
[79]
Sun M, Shi H, Liu C, et al. Construction and evaluation of a novel humanized HER2-specific chimeric receptor[J]. Breast Cancer Res 2014, 16(3): R61.
[80]
U.S. National Institutes of Health. EpCAM CAR-T for treatment of nasopharyngeal carcinoma and breast cancer[EB/OL]. [2017-09-10].

URL    
[81]
U.S. National Institutes of Health. Chimeric antigen receptor-modified T Cells for breast cancer [EB/OL].[2017-09-10].

URL    
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