人结直肠癌和肿瘤引流淋巴结组织中Foxp3~+调节性T细胞和髓样树突状细胞的表达及其意义
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摘要
目的:探讨Foxp3~+ 调节性T细胞(Tregs)和CD11c~+髓样树突状细胞(mDCs)在结直肠癌(CRC)组织中的表达及在肿瘤引流淋巴结(TDLN)组织中的浸润,并探讨其临床意义。方法:收集CRC患者手术切除的标本52例,采用免疫组织化学方法检测CRC患者标本及TDLN组织样本中Foxp3~+ Tregs及CD11c~+mDCs的表达,并探讨其表达频数与CRC患者临床病理特征的关系。结果:CRC患者癌组织中Foxp3~+ Tregs的阳性表达频数高于癌旁正常组织(P<0.01);淋巴结转移阳性者癌组织中Foxp3~+ Tregs阳性表达频数高于淋巴结转移阴性者(P<0.01);TNM分期Ⅲ+Ⅳ期组患者癌组织中Foxp3~+ Tregs阳性表达频数高于TNM分期Ⅰ+Ⅱ期组患者(P<0.01);肿瘤引流阳性淋巴结(mTDLN)组织中Foxp3~+ Tregs阳性表达频数明显高于肿瘤引流阴性淋巴结(mfTDLN)组织(P<0.01)。CRC患者癌组织中CD11c~+mDCs的阳性表达频数高于癌旁正常组织(P<0.01);淋巴结转移阳性者癌组织中CD11c~+mDCs阳性表达频数低于淋巴结转移阴性者(P<0.01);TNM分期Ⅲ+Ⅳ期组患者癌组织中CD11c~+mDCs阳性表达频数低于TNM分期Ⅰ+Ⅱ期组患者(P<0.01);不同浸润深度癌组织中CD11c~+mDCs阳性表达频数比较差异有统计学意义(P<0.05);mTDLN组织中CD11c~+mDCs阳性表达频数明显低于mfTDLN组织(P<0.01)。CRC和TDLN组织中Foxp3~+ Tregs表达与CD11c~+mDCs的表达无相关性(P>0.05)。结论:CRC的发生发展与癌组织局部微环境中Foxp3~+ Tregs及CD11c~+mDCs的表达频数有关。Foxp3~+ Tregs和CD11c~+mDCs在抑制肿瘤微环境的细胞免疫中发挥作用。
Objective:To explore the expressions of Foxp3~+ Tregs and CD11c~+ mDCs in the colorectal cancer(CRC)tissue and their infiltrations in the tumor draining lymph node(TDLN)tissue,and to explore the clinical significances.Methods:Fifty-two samples of surgical resection of the CRC patients were collected.The expressions of Foxp3~+ Tregs and CD11c~+ mDCs in the specimens of the CRC patients and TDLN tissue were detected by immunohistochemistry,and the relationship between the expression frequencies of Foxp3~+ Tregs and CD11c~+ mDCs and the clinicopathological characteristics of the patients were discussed.Results:The positive expression frequency of Foxp3~+ Tregs in cancer tissue of the CRC patients was higher than that in adjacent normal mucosa tissue(P<0.01);The expression frequency of Foxp3~+ Tregs in cancer tissue in the patients with positive lymph node metastasis was higher than that in the patients with negative lymph node metastasis(P<0.01);the expression frequency of Foxp3~+ Tregs in the patients in TNM stageⅢ+Ⅳ was higher than that in TNM stageⅠ+Ⅱ(P<0.01);the positive expression frequency of Foxp3~+ Tregs in metastatic TDLN(mTDLN)tissue was higher than that in metastatic free TDLN(mfTDLN)tissue(P<0.01).The positive expression frequency of CD11c~+ mDCs in cancer tissue of the CRC patients was higher than that in adjacent normal mucosa tissue(P<0.01);the positive expression frequency of CD11c~+ mDCs in the patients with positive lymph node metastasis was lower than that in the patients with negative lymph node metastasis(P<0.01);the positive expression frequency of CD11c~+ mDCs in the patients in TNM stageⅢ+Ⅳ was lower than that in the patients in TNM stageⅠ+Ⅱ(P<0.01);the positive expression frequencies of CD11c~+ mDCs in cancer tissue with different depths invasion were significantly different(P<0.05);the positive expression frequency of CD11c~+ mDCs in mTDLN tissue was lower than that in mfTDLN tissue(P <0.01).There were no significant correlations between the expressions of Foxp3~+ Tregs and CD11c~+ mDCs in the CRC and TDLN tissues(P>0.05).Conclusion:The occurrence and development of CRC are related to the changes of Foxp3~+ Tregs and CD11c~+ mDCs expression frequencies in the local microenvironment of cancer tissue.Foxp3~+ Tregs and CD11c~+ mDCs play a role in inhibiting the cellular immunity in tumor microenvironment.
Objective:To explore the expressions of Foxp3~+ Tregs and CD11c~+ mDCs in the colorectal cancer(CRC)tissue and their infiltrations in the tumor draining lymph node(TDLN)tissue,and to explore the clinical significances.Methods:Fifty-two samples of surgical resection of the CRC patients were collected.The expressions of Foxp3~+ Tregs and CD11c~+ mDCs in the specimens of the CRC patients and TDLN tissue were detected by immunohistochemistry,and the relationship between the expression frequencies of Foxp3~+ Tregs and CD11c~+ mDCs and the clinicopathological characteristics of the patients were discussed.Results:The positive expression frequency of Foxp3~+ Tregs in cancer tissue of the CRC patients was higher than that in adjacent normal mucosa tissue(P<0.01);The expression frequency of Foxp3~+ Tregs in cancer tissue in the patients with positive lymph node metastasis was higher than that in the patients with negative lymph node metastasis(P<0.01);the expression frequency of Foxp3~+ Tregs in the patients in TNM stageⅢ+Ⅳ was higher than that in TNM stageⅠ+Ⅱ(P<0.01);the positive expression frequency of Foxp3~+ Tregs in metastatic TDLN(mTDLN)tissue was higher than that in metastatic free TDLN(mfTDLN)tissue(P<0.01).The positive expression frequency of CD11c~+ mDCs in cancer tissue of the CRC patients was higher than that in adjacent normal mucosa tissue(P<0.01);the positive expression frequency of CD11c~+ mDCs in the patients with positive lymph node metastasis was lower than that in the patients with negative lymph node metastasis(P<0.01);the positive expression frequency of CD11c~+ mDCs in the patients in TNM stageⅢ+Ⅳ was lower than that in the patients in TNM stageⅠ+Ⅱ(P<0.01);the positive expression frequencies of CD11c~+ mDCs in cancer tissue with different depths invasion were significantly different(P<0.05);the positive expression frequency of CD11c~+ mDCs in mTDLN tissue was lower than that in mfTDLN tissue(P <0.01).There were no significant correlations between the expressions of Foxp3~+ Tregs and CD11c~+ mDCs in the CRC and TDLN tissues(P>0.05).Conclusion:The occurrence and development of CRC are related to the changes of Foxp3~+ Tregs and CD11c~+ mDCs expression frequencies in the local microenvironment of cancer tissue.Foxp3~+ Tregs and CD11c~+ mDCs play a role in inhibiting the cellular immunity in tumor microenvironment.
引文
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[22]THOMAS S N,VOKALI E,LUND A W,et al.Targeting the tumor-draining lymph node with adjuvanted nanoparticles reshapes the anti-tumor immune response[J].Biomaterials,2014,35(2):814-824.
[23]BRACAMONTE-BARAN W,FLORENTIN J,ZHOU Y,et al.Modification of host dendritic cells by microchimerismderived extracellular vesicles generates split tolerance[J].Proc Natl Acad Sci U S A,2017,114(5):1099-1104.
[2]FONTENOT J D,GAVIN M A,RUDENSKY A Y.Foxp3programs the development and function of CD4+CD25+regulatory T cells[J].Nat Immunol,2003,4(4):330-336.
[3]KHATTRI R,COX T,YASAYKO S A,et al.An essential role for Scurfin in CD4+CD25+T regulatory cells[J].Nat Immunol,2003,4(4):337-342.
[4]TANAKA A,SAKAGUCHI S.Regulatory T cells in cancer immunotherapy[J].Cell Res,2017,27(1):109-118.
[5]ELEONORA T,ILENIA P,VALERIA S,et al.Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer Oncoimmunology[J].Oncoimmunology,2016,5(7):e1175800.
[6]GILLIET M,LIU Y J.Human plasmacytoid-derived dendritic cells and the induction of T-regulatory cells[J].Hum Immunol,2002,63(12):1149-1155.
[7]MOSEMAN E A,LIANG X Q,DAWSON A J,et al.Human plasmacytoid dendritic cells activated by CpGoligodeoxynucleotides induce the generation of CD4+CD25+regulatory T cells[J].J Immunol,2004,173(7):4433-4442.
[8]SUN C M,HALL J A,BLANK R B,et al.Small intestine lamina propria dendritic cells promote de novo generation of Foxp3Treg cells via retinoic acid[J].J Exp Med,2007,204(8):1775-1785.
[9]PALUCKA K,UENO H,FAY J,et al.Dendritic cells and immunity against cancer[J].J Intern Med,2011,269(1):64-73.
[10]TARBELL K V,PETIT L,ZUO X,et al.Dendritic cellexpanded,islet-specific CD4+CD25+CD62L+regulatory Tcells restore normoglycemia in diabetic NOD mice[J].J Exp Med,2007,204(1):191-201.
[11]LIU Y J.A unified theory of central tolerance in the thymus[J].Trends Immunol,2006,27(5):215-221.
[12]SHI C,ZHANG Y,YANG H,et al.Ultrasound-targeted microbubble destruction-mediated Foxp3 knockdown may suppress the tumor growth of HCC mice by relieving immunosuppressive Tregs function[J].Exp Ther Med,2018,15(1):31-38.
[13]WOO E Y,CHU C S,GOLETZ T J,et al.Regulatory CD4+CD25+T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer[J].Cancer Res,2001,61(12):4766-4772.
[14]LIYANAGE U K,MOORE T T,JOO H G,et al.Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma[J].J Immunol,2002,169(5):2756-2761.
[15]YAMAZAKI S,PATEL M,HARPER A,et al.Effective expansion of alloantigen-specific Foxp3+CD25+CD4+regulatory T cells by dendritic cells during the mixed leukocyte reaction[J].Proc Natl Acad Sci U S A,2006,103(8):2758-2763.
[16]YU A X,SNOWHITE I,VENDRAME F,et al.Selective IL-2responsiveness of regulatory T cells through multiple intrinsic mechanisms supports the use of low-dose IL-2therapy in type 1diabetes[J].Diabetes,2015,64(6):2172-2183.
[17]SHI C Y,ZHANG Y,YANG H C,et al.Ultrasoundtargeted microbubble destruction-mediated Foxp3knockdown may suppress the tumor growth of HCC mice by relieving immunosuppressive Tregs function[J].Exp Ther Med,2018,15(1):31-38.
[18]SATO E,OLSON S H,AHN J,et al.Intraepithelial CD8+tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer[J].Proc Natl Acad Sci U S A,2005,102(51):18538-18543.
[19]TROJANDT S,BELLINGHAUSEN I,RESKE-KUNZ A B,et al.Tumor-derived immuno-modulators induce overlapping pro-tolerogenic gene expression signatures in human dendritic cells[J].Hum Immunol,2016,77(12):1223-1231.
[20]LEGITIMO A,CONSOLINI R,FAILL A,et al.Dendritic cell defects in the colorectal cancer[J].Human vaccines Immunotherapeut,2014,10(11):3224-3235.
[21]LOHELA M,CASBON A J,OLOW A,et al.Intravital imaging reveals distinct responses of depleting dynamic tumorassociated macrophage and dendritic cell subpopulations[J].Proc Natl Acad Sci U S A,2014,111(47):E5086-E5095.
[22]THOMAS S N,VOKALI E,LUND A W,et al.Targeting the tumor-draining lymph node with adjuvanted nanoparticles reshapes the anti-tumor immune response[J].Biomaterials,2014,35(2):814-824.
[23]BRACAMONTE-BARAN W,FLORENTIN J,ZHOU Y,et al.Modification of host dendritic cells by microchimerismderived extracellular vesicles generates split tolerance[J].Proc Natl Acad Sci U S A,2017,114(5):1099-1104.