非小细胞肺癌患者的肿瘤转移与肿瘤浸润的CD8~+T细胞数量负相关
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摘要
目的分析非小细胞肺癌(NSCLC)患者原位肿瘤中浸润T细胞数量与临床转移及患者临床预后的关系。方法选取肺癌组织共140例(其中发生转移的43例),采用免疫组织化学染色法检测肿瘤组织中CD4~+ T细胞和CD8~+ T细胞在肿瘤组织的浸润情况,对比未转移和转移患者肿瘤组织CD4~+T细胞和CD8~+ T细胞的浸润数量,采用生存分析对比不同CD4~+ T细胞和CD8~+ T细胞浸润数量对患者临床预后的影响。结果两组患者肿瘤组织CD4~+ T细胞比例差异不大,转移组患者肿瘤组织CD8~+ T细胞数量显著低于转移组,且未转移组CD8/CD4比例显著高于转移组, CD8~+ T细胞数量多和CD8/CD4比例高的患者总体生存率显著优于CD8~+ T细胞数量少和CD8/CD4比例低的患者。结论出现转移的NSCLC患者肿瘤组织CD8~+ T细胞浸润数量、 CD8/CD4比例均显著下降,与NSCLC转移患者预后差密切相关。
Objective To analyze the relationship between the number of invasive T cells in in situ tumors and the clinical metastasis and prognosis in patients with non-small cell lung cancer(NSCLC). Methods A total of 140 lung cancer patients(including 43 cases with metastasis) were selected to observe the infiltration state of CD4~+ T cells and CD8~+ T cells in tumor tissues by immunohistochemical staining. The infiltration of CD4~+ T cells and CD8~+ T cells were compared between non-metastatic and metastatic patients. The effects of different infiltration levels of CD4~+ T cells and CD8~+ T cells on clinical prognosis were analyzed. Results The proportion of CD4~+ T cells in the tumor tissues of the two groups was not significantly different. The number of CD8~+ T cells in the metastatic group was significantly lower than that in the metastatic group, and the ratio of CD8/CD4 in the non-metastasis group was remarkably higher than that in the metastatic group. Patients with high CD8~+ T cell infiltration level or high ratio of CD8/CD4 have a significantly better overall survival rate than the patients with low CD8~+ T cell infiltration level or low ratio of CD8/CD4. Conclusion The number of CD8~+ T cell infiltration and CD8/CD4 ratio in the tumor tissues of patients with metastatic NSCLC are significantly reduced, which is closely related to the poor prognosis of patients with NSCLC metastasis.
Objective To analyze the relationship between the number of invasive T cells in in situ tumors and the clinical metastasis and prognosis in patients with non-small cell lung cancer(NSCLC). Methods A total of 140 lung cancer patients(including 43 cases with metastasis) were selected to observe the infiltration state of CD4~+ T cells and CD8~+ T cells in tumor tissues by immunohistochemical staining. The infiltration of CD4~+ T cells and CD8~+ T cells were compared between non-metastatic and metastatic patients. The effects of different infiltration levels of CD4~+ T cells and CD8~+ T cells on clinical prognosis were analyzed. Results The proportion of CD4~+ T cells in the tumor tissues of the two groups was not significantly different. The number of CD8~+ T cells in the metastatic group was significantly lower than that in the metastatic group, and the ratio of CD8/CD4 in the non-metastasis group was remarkably higher than that in the metastatic group. Patients with high CD8~+ T cell infiltration level or high ratio of CD8/CD4 have a significantly better overall survival rate than the patients with low CD8~+ T cell infiltration level or low ratio of CD8/CD4. Conclusion The number of CD8~+ T cell infiltration and CD8/CD4 ratio in the tumor tissues of patients with metastatic NSCLC are significantly reduced, which is closely related to the poor prognosis of patients with NSCLC metastasis.
引文
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[3] Guo W,Liu S,Zhang X,et al.The coexpression of multi-immune inhibitory receptors on T lymphocytes in primary non-small-cell lung cancer[J].Drug Des Devel Ther,2017,28(11):3367-3376.
[4] Kinoshita T,Kudo-Saito C,Muramatsu R,et al.Determination of poor prognostic immune features of tumour microenvironment in non-smoking patients with lung adenocarcinoma[J].Eur J Cancer,2017,86:15-27.
[5] Xia L,Liu Y,Wang Y.PD-1/PD-L1 blockade therapy in advanced non-small-cell lung cancer:Current status and future directions[J].Oncologist,2019,24(Suppl 1):S31-S41.
[6] Müller P,Martin K,Theurich S,et al.Microtubule-depolymerizing agents used in antibody-drug conjugates induce antitumor immunity by stimulation of dendritic cells[J].Cancer Immunol Res,2014,2(8):741-755.
[7] Passiglia F,Commendatore O,Vitali M,et al.Immunotherapy in non-small-cell lung cancer:a bridge between research and clinical practice[J].Future Oncol,2018,14(13s):41-60.
[8] Simsek M,Tekin S B,Bilici M.Immunological agents used in cancer treatment[J].Eurasian J Med,2019,51(1):90-94.
[9] Ries C H,Cannarile M A,Hoves S,et al.Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy[J].Cancer Cell,2014,25(6):846-859.
[10] Zhuo M,Chen H,Zhang T,et al.The potential predictive value of circulating immune cell ratio and tumor marker in atezolizumab treated advanced non-small cell lung cancer patients[J].Cancer Biomark,2018,22(3):467-476.
[11] Djenidi F,Adam J,Goubar A,et al.CD8+CD103+ tumor-infiltrating lymphocytes are tumor-specific tissue-resident memory T cells and a prognostic factor for survival in lung cancer patients[J].J Immunol,2015,194(7):3475-3486.
[12] Bald T,Landsberg J,Lopez-Ramos D,et al.Immune cell poor melanomas benefit from PD-1 blockade after targeted type Ⅰ IFN activation[J].Cancer Discov,2014,4(6):674-687.
[13] Watanabe S,Hayashi H,Haratani K,et al.Mutational activation of the epidermal growth factor receptor down-regulates major histocompatibility complex class Ⅰ expression via the extracellular signal-regulated kinase in non-small cell lung cancer[J].Cancer Sci,2019,110(1):52-60.
[14] Gu L,Chen M,Guo D,et al.PD-L1 and gastric cancer prognosis:A systematic review and meta-analysis[J/OL].PLoS One,2017,12(8):e0182692.DOI:10.1371/journal.pone.0182692.eCollection 2017.
[15] Gong B,Kiyotani K,Sakata S,et al.Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non-small cell lung cancer[J].J Exp Med,2019(14):982-1000.
[16] Kamphorst A O,Pillai R N,Yang S,et al.Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients[J].Proc Natl Acad Sci U S A,2017,114(19):4993-4998.
[17] Lo Presti E,Dieli F,Meraviglia S.Tumor-infiltrating γδ T lymphocytes:pathogenic role,clinical significance,and differential programing in the tumor microenvironment[J/OL].Front Immunol,2014,24(5):607.DOI:10.3389/fimmu.2014.00607.eCollection 2014.
[18] Stankovic B,Bjrhovde H A K,Skarshaug R,et al.Immune cell composition in human non-small cell lung cancer[J/OL].Front Immunol,2019,1(9):3101.DOI:10.3389/fimmu.2018.03101
[19] Lin Z,Gu J,Cui X,et al.Deciphering microenvironment of NSCLC based on CD8+ TIL density and PD-1/PD-L1 expression[J].J Cancer,2019,10(1):211-222.
[20] Chae Y K,Chang S,Ko T,et al.Epithelial-mesenchymal transition (EMT) signature is inversely associated with T-cellinfiltration in non-small cell lung cancer (NSCLC)[J/OL].Sci Rep,2018,8(1):2918.DOI:10.1038/s41598-018-21061-1.
[21] Zheng H,Liu X,Zhang J,et al.Expression of PD-1 on CD4+ T cells in peripheral blood associates with poor clinical outcome in non-small cell lung cancer[J].Oncotarget,2016,7(35):56233-56240.
[22] Sheng S Y,Gu Y,Lu C G,et al.The distribution and function of human memory T cell subsets in lung cancer[J].Immunol Res,2017,65(3):639-650.
[23] Müller P,Rothschild S I,Arnold W,et al.Metastatic spread in patients with non-small cell lung cancer is associated with a reduced density of tumor-infiltrating T cells[J].Cancer Immunol Immunother,2016,65(1):1-11.
[24] Chen X,Zhang W,Qian D,et al.Chemoradiotherapy-induced CD4+ and CD8+ T-cell alterations to predict patient outcomes in esophageal squamous cell carcinoma[J/OL].Front Oncol,2019,15(9):73.DOI:10.3389/fonc.2019.00073.
[25] Khan H,Pillarisetty V G,Katz S C.The prognostic value of liver tumor T cell infiltrates[J].J Surg Res,2014,191(1):189-195.