AFP阳性胃癌局部免疫状况的初步研究
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摘要
目的:分析树突状细胞(DC)、调节性T细胞(Treg)、细胞毒性T淋巴细胞(CTL)及NK细胞在AFP阳性胃癌(AFP~+GC)肿瘤微环境中的浸润水平,并与AFP阴性胃癌(AFP-GC)进行对比,借以探讨AFP~+GC的局部免疫状况及其临床意义。方法:利用S-100蛋白、FOXP3和GZMB抗体通过免疫组化分别检测31例AFP~+GC与65例AFP-GC患者肿瘤微环境中S-100~+DC、Foxp3~+Treg、GZMB~+CTL和GZMB~+NK细胞的浸润水平,比较两组患者在局部免疫状况上的差异性。结果:AFP~+GC肿瘤微环境中的S-100~+DC、GZMB~+CTL及GZMB~+NK细胞浸润数量明显少于AFP-GC(P<0. 05),而Foxp3~+Treg浸润数量明显多于AFP-GC(P<0. 05),且还与部分临床病理因素有关。结论:AFP~+GC与AFP-GC相比,以S-100~+DC、GZMB~+CTL、GZMB~+NK细胞为代表的正向免疫调节能力更弱,而以Foxp3~+Treg为代表的负向免疫调节能力更强,且DC等免疫细胞的浸润水平与其临床病理因素存在一定关系。
Objective: The infiltration level of dendritic cells( DC),regulatory T cells( Treg),cytotoxic T-lymphocytes( CTL and nature killer cells( NK cells) in the tumor microenvironment of alpha-fetoprotein positive gastric cancer( AFP~+GC) was analyzed,and compared with alpha-fetoprotein negative gastric cancer( AFP-GC),to explore the local immune status of AFP~+GC and its clinical significance. Methods: The infiltration levels of S-100~+DC,Foxp3~+Treg,GZMB~+CTL and GZMB~+NK cells in the tumor microenvironment of 31 patients with AFP~+GC and 65 patients with AFP-GC were respectively detected by immunohistochemistry with S-100,FOXP3 and GZMB antibodies. Then the differences in local immune status between the two groups were compared. Results: The infiltration amount of S-100~+DC,GZMB~+CTL and GZMB~+NK cells in the tumor microenvironment of AFP~+GC was significantly lower than that of AFP-GC( P<0. 05),but the infiltration of Foxp3~+Treg was significantly higher than that of AFP-GC( P<0. 05),and it' s also related to some clinicopathological factors. Conclusion: Compared with AFP-GC,AFP~+GC was weaker in the positive immunoregulation capacity represented by S-100~+DC,GZMB~+CTL and GZMB~+NK cells,while the negative immunoregulation capacity represented by Foxp3~+Treg was enhanced. Moreover,the infiltration level of immune cells such as DC is related to its clinicopathological factors.
Objective: The infiltration level of dendritic cells( DC),regulatory T cells( Treg),cytotoxic T-lymphocytes( CTL and nature killer cells( NK cells) in the tumor microenvironment of alpha-fetoprotein positive gastric cancer( AFP~+GC) was analyzed,and compared with alpha-fetoprotein negative gastric cancer( AFP-GC),to explore the local immune status of AFP~+GC and its clinical significance. Methods: The infiltration levels of S-100~+DC,Foxp3~+Treg,GZMB~+CTL and GZMB~+NK cells in the tumor microenvironment of 31 patients with AFP~+GC and 65 patients with AFP-GC were respectively detected by immunohistochemistry with S-100,FOXP3 and GZMB antibodies. Then the differences in local immune status between the two groups were compared. Results: The infiltration amount of S-100~+DC,GZMB~+CTL and GZMB~+NK cells in the tumor microenvironment of AFP~+GC was significantly lower than that of AFP-GC( P<0. 05),but the infiltration of Foxp3~+Treg was significantly higher than that of AFP-GC( P<0. 05),and it' s also related to some clinicopathological factors. Conclusion: Compared with AFP-GC,AFP~+GC was weaker in the positive immunoregulation capacity represented by S-100~+DC,GZMB~+CTL and GZMB~+NK cells,while the negative immunoregulation capacity represented by Foxp3~+Treg was enhanced. Moreover,the infiltration level of immune cells such as DC is related to its clinicopathological factors.
引文
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[2] He R,Yang Q,Dong X,et al. Clinicopathologic and prognostic characteristics of alpha-fetoprotein-producing gastric cancer[J].Oncotarget,2017,8(14):23817-23830.
[3] Chen Y,Qu H,Jian M,et al. High level of serum AFP is an independent negative prognostic factor in gastric cancer[J]. Int J Biol Markers,2015,30(4):e387-e393.
[4]温世军,刘忠,胡祥.血清甲胎蛋白阳性胃癌患者的临床特点及预后分析[J].中华胃肠外科杂志,2016,19(1):67-70.Wen SJ,Liu Z,Hu X. Clinical features and prognostic analysis of alpha-fetoprotein positive gastric cancer[J]. Chin J Gagtrointestinal Surg,2016,19(1):67-70.
[5] Zuo CT,Ju Q. An analysis of clinical characteristics and prognosis for patients with serum alpha-fetoprotein-positive gastric cancer[J]. Minerva Med,2015,106(4):185-191.
[6] Wilson NS, El-Sukkari D, Villadangos JA. Dendritic cells constitutively present self antigens in their immature state in vivo and regulate antigen presentation by controlling the rates of MHC class II synthesis and endocytosis[J]. Blood,2004,103(6):2187-2195.
[7]龚非力,沈关心,李卓娅,等.医学免疫学[M].第3版.北京:科学出版社,2009:106-112.Gong FL,Shen GX,Li ZY,et al. Medical immunology[M]. 3th Edition. Beijing:Science Press,2009:106-112.
[8] Soukup K,Halfmann A,Dillinger B,et al. Loss of MAPK-activated protein kinase 2 enables potent dendritic cell-driven anti-tumour T cell response[J]. Sci Rep,2017,7(1):11746.
[9] Li R,Fang F,Jiang M,et al. STAT3 and NF-κB are simultaneously suppressed in dendritic cells in lung cancer[J]. Sci Rep,2017,7:45395.
[10] Tang M,Diao J,Cattral M. Molecular mechanisms involved in dendritic cell dysfunction in cancer[J]. Cell Mol Life Sci,2017,74(5):761-776.
[11] Chae C,Teran-Cabanillas E,Cubillos-Ruiz J. Dendritic cell rehab:new strategies to unleash therapeutic immunity in ovarian cancer[J]. Cancer Immunol Immunother,2017,66(8):969-977.
[12] Legitimo A,Consolini R,Failli A,et al. Dendritic cell defects in the colorectal cancer[J]. Hum Vaccin Immunother,2014,10(11):3224-3235.
[13] Tsujitani S,Kakeji Y,Watanabe A,et al. Infiltration of dendritic cells in relation to tumor invasion and lymph node metastasis in human gastric cancer[J]. Cancer,1990,66(9):2012-2016.
[14] Wang Y,Xu B,Hu W,et al. High expression of CD11c indicates favorable prognosis in patients with gastric cancer[J]. World J Gastroenterol,2015,21(31):9403-9412.
[15] Ishigami S,Natsugoe S,Tokuda K,et al. Clinical impact of intratumoral natural killer cell and dendritic cell infiltration in gastric cancer[J]. Cancer Lett,2000,159(1):103-108.
[16] Pirtskhalaishvili G,Shurin G,Gambotto A,et al. Transduction of dendritic cells with Bcl-xL increases their resistance to prostate cancer-induced apoptosis and antitumor effect in mice[J]. J Immunol,2000,165(4):1956-1964.
[17] Iwamoto M,Shinohara H,Miyamoto A,et al. Prognostic value of tumor-infiltrating dendritic cells expressing CD83 in human breast carcinomas[J]. Int J Cancer,2003,104(1):92-97.
[18] Lijun Z,Xin Z,Danhua S,et al. Tumor-infiltrating dendritic cells may be used as clinicopathologic prognostic factors in endometrial carcinoma[J]. Int J Gynecol Cancer,2012,22(5):836-841.
[19] Gulubova M,Ananiev J,Vlaykova T,et al. Role of dendritic cells in progression and clinical outcome of colon cancer[J]. Int J Colorectal Dis,2012,27(2):159-169.
[20] Pereira LMS,Gomes STM,Ishak R,et al. Regulatory T cell and forkhead box protein 3 as modulators of immune homeostasis[J].Front Immunol,2017,8:605.
[21] Edelblum KL. Dissecting the requirement for secondary lymphoid organs in peripheral regulatory T-cell development[J]. Cell Mol Gastroenterol Hepatol,2016,2(3):253-254.
[22] Hu SX,Wang S,Wang JP,et al. Expression of endogenous Granzyme B in a subset of human primary breast carcinomas[J].Br J Cancer,2003,89(1):135-139.
[23] Hwang H,Kim H,Kim S,et al. Prognostic impact of the tumor-infiltrating regulatory T-cell(Foxp3+)/activated cytotoxic T lymphocyte(granzyme B+)ratio on resected left-sided pancreatic cancer[J]. Oncol Lett,2016,12(6):4477-4484.
[24] Shibutani M,Maeda K,Nagahara H,et al. The prognostic significance of the tumor-infiltrating programmed cell death-1+to CD8+lymphocyte ratio in patients with colorectal cancer[J].Anticancer Res,2017,37(8):4165-4172.
[25] Sokol L,Koelzer V,Rau T,et al. Loss of tapasin correlates with diminished CD8(+)T-cell immunity and prognosis in colorectal cancer[J]. J Transl Med,2015,13:279.
[26] Jin S,Deng Y,Hao J,et al. NK cell phenotypic modulation in lung cancer environment[J]. PLo S One,2014,9(10):e109976.
[27] Alvarez-Dominguez C,Calderón-Gonzalez R,Terán-Navarro H,et al. Dendritic cell therapy in melanoma[J]. Ann Transl Med,2017,5(19):386.
[28] Yeku O,Slovin S. Immune therapy for prostate cancer[J]. Cancer J,2016,22(5):334-341.
[29] Berry J,Vreeland T,Trappey A,et al. Cancer vaccines in colon and rectal cancer over the last decade:lessons learned and future directions[J]. Exp Rev Clin Immunol,2017,13(3):235-245.
[30] Mu Y,Zhou C,Chen S,et al. Effectiveness and safety of chemotherapy combined with cytokine-induced killer cell/dendritic cell-cytokine-induced killer cell therapy for treatment of gastric cancer in China:A systematic review and meta-analysis[J]. Cytotherapy,2016,18(9):1162-1177.
[31] Anguille S,Smits E,Lion E,et al. Clinical use of dendritic cells for cancer therapy[J]. Lancet Oncol,2014,15(7):e257-e267.
[32] Lee J,Lee Y,Lee M,et al. A phaseⅠ/Ⅱa study of adjuvant immunotherapy with tumour antigen-pulsed dendritic cells in patients with hepatocellular carcinoma[J]. Br J Cancer,2015,113(12):1666-1676.
[33] Chaudhary B,Abd Al Samid M,al-Ramadi B,et al. Phenotypic alterations,clinical impact and therapeutic potential of regulatory T cells in cancer[J]. Exp Opin Biol Ther,2014,14(7):931-945.
[34] Voena C,Chiarle R. Advances in cancer immunology and cancer immunotherapy[J]. Discov Med,2016,21(114):125-133.
[35] Kazandjian D,Suzman D,Blumenthal G,et al. FDA approval summary:nivolumab for the treatment of metastatic non-small cell lung cancer with progression on or after platinum-based chemotherapy[J]. Oncologist,2016,21(5):634-642.
[36] Linck R,Costa R,Garicochea B. Cancer immunology and melanoma immunotherapy[J]. An Bras Dermatol,2017,92(6):830-835.
[37] Mendiratta P,Rini B,Ornstein M. Emerging immunotherapy in advanced renal cell carcinoma[J]. Urol Oncol,2017,35(12):687-693.
[38] Kavunja H,Lang S,Sungsuwan S,et al. Delivery of foreign cytotoxic T lymphocyte epitopes to tumor tissues for effective antitumor immunotherapy against pre-established solid tumors in mice[J]. Cancer Immunol Immunother,2017,66(4):451-460.