肿瘤相关成纤维细胞对头颈部鳞状细胞癌肿瘤浸润免疫细胞的调控作用及机制探讨

doi:10.19438/j.cjoms.2023.02.003

中国口腔颌面外科杂志 ›› 2023, Vol. 21 ›› Issue (2): 119-124.doi: 10.19438/j.cjoms.2023.02.003

肿瘤相关成纤维细胞对头颈部鳞状细胞癌肿瘤浸润免疫细胞的调控作用及机制探讨

韩林孜^1,2, 周建华¹, 赵谦³, 董磊^1,2, 陈正岗¹, 邱建忠¹, 袁荣涛¹

1.青岛市市立医院口腔医学中心,山东青岛 266071;
2.大连医科大学研究生院,辽宁大连 116044;
3.青岛大学口腔医学院,山东青岛 266003

收稿日期:2022-12-04 修回日期:2022-12-29 出版日期:2023-03-20 发布日期:2023-06-12
通讯作者: 袁荣涛,E-mail：yuanrongtao@163.com
作者简介:韩林孜（1995-）,男,硕士,医师,E-mail：351544159@qq.com

The regulation and mechanism of cancer-associated fibroblasts on tumor-infiltrating immune cells in head and neck squamous cell carcinoma

HAN Lin-zi^1,2, ZHOU Jian-hua¹, ZHAO Qian³, DONG Lei^1,2, CHEN Zheng-gang¹, QIU Jian-zhong¹, YUAN Rong-tao¹

1. The Center of Stomatology, Qingdao Municipal Hospital. Qingdao 266071, Shandong Province;
2. Graduate School, Dalian Medical University. Dalian 116044, Liaoning Province;
3. School of Stomatology, Qingdao University. Qingdao 266003, Shandong Province, China

Received:2022-12-04 Revised:2022-12-29 Online:2023-03-20 Published:2023-06-12

摘要/Abstract

摘要： 目的： 探讨在头颈部鳞状细胞癌（head and neck squamous cell carcinoma,HNSCC）中肿瘤相关成纤维细胞（cancer-associated fibroblasts,CAFs）对肿瘤浸润免疫细胞的调控作用。方法： 通过TCGA数据库及临床肿瘤样本,获取与HNSCC相关的lncRNA MIR99AHG的表达谱及相关临床数据。对CAFs及正常成纤维细胞（normal fibroblasts,NFs）进行原代培养及鉴定。qRT-PCR检测与CAFs或NFs共培养的舌鳞癌细胞中lncRNA MIR99AHG的表达情况。对HNSCC中lncRNA MIR99AHG与肿瘤浸润免疫细胞的相关性进行分析。采用Graph Pad 8.0.2对数据进行统计学分析。结果： lncRNA MIR99AHG在HNSCC中低表达,且基因高表达与预后呈正相关。Western免疫印迹显示,CAFs中α-SMA高表达。qRT-PCR显示,相比阴性对照组,与CAFs共培养的舌鳞癌细胞中lncRNA MIR99AHG的表达显著降低。lncRNA MIR99AHG与T细胞、CD8⁺ T细胞、B细胞、NK细胞等呈正相关,而与Th1、Th2、中性粒细胞、Tgd等呈负相关。结论： CAFs通过抑制HNSCC中lncRNA MIR99AHG的表达,从而调控肿瘤浸润免疫细胞的表达。

关键词: 头颈部鳞状细胞癌, lncRNA, 肿瘤相关成纤维细胞, 肿瘤浸润免疫细胞

Abstract: PURPOSE: To explore the mechanism of cancer-associated fibroblasts (CAFs) regulating the expression of tumor-infiltrating immune cells in head and neck squamous cell carcinoma (HNSCC). METHODS: The expression profile and clinical data analysis of lncRNA MIR99AHG related to HNSCC were obtained through the TCGA database, and clinical tumor samples. Primary cell culture and identification of CAFs and normal fibroblasts(NFs) were taken. The expression of lncRNA MIR99AHG in tongue cancer cells co-cultured with CAFs or NFs were detected by qRT-PCR. Correlation of lncRNA MIR99AHG in HNSCC and tumor-infiltrating immune cells was analyzed with Graph Pad 8.0.2 software. RESULTS: LncRNA MIR99AHG was a low expression gene in HNSCC and high expression of lncRNA MIR99AHG was positively correlated with prognosis. Western blot analysis showed that α-SMA was highly expressed in CAFs. qRT-PCR showed that the expression of lncRNA MIR99AHG in tongue cancer cells co-cultured with CAFs was significantly downregulated compared with the negative control group. LncRNA MIR99AHG was positively correlated with T cells, CD8⁺ T cells, B cells, NK cells, but negatively correlated with Th1, Th2, neutrophils, Tgd. CONCLUSIONS: CAFs may inhibit the expression of lncRNA MIR99AHG to regulate the expression of tumor-infiltrating immune cells in HNSCC.

Key words: Head and neck squamous cell carcinoma, lncRNA, Cancer-associated fibroblast, Tumor-infiltrating immune cells

中图分类号:

R739.8

韩林孜, 周建华, 赵谦, 董磊, 陈正岗, 邱建忠, 袁荣涛. 肿瘤相关成纤维细胞对头颈部鳞状细胞癌肿瘤浸润免疫细胞的调控作用及机制探讨[J]. 中国口腔颌面外科杂志, 2023, 21(2): 119-124.

HAN Lin-zi, ZHOU Jian-hua, ZHAO Qian, DONG Lei, CHEN Zheng-gang, QIU Jian-zhong, YUAN Rong-tao. The regulation and mechanism of cancer-associated fibroblasts on tumor-infiltrating immune cells in head and neck squamous cell carcinoma[J]. China J Oral Maxillofac Surg, 2023, 21(2): 119-124.

参考文献

[1] Johnson DE, Burtness B, Leemans CR, et al.Head and neck squamous cell carcinoma[J]. Nat Rev Dis Primers, 2020, 6(1): 92-140.
[2] Elmusrati A, Wang J, Wang CY.Tumor microenvironment and immune evasion in head and neck squamous cell carcinoma[J]. Int J Oral Sci, 2021, 13(1): 24-34.
[3] Wang G, Zhang M, Cheng M, et al.Tumor microenvironment in head and neck squamous cell carcinoma: functions and regulatory mechanisms[J]. Cancer Lett, 2021, 507: 55-69.
[4] Li B, Ren M, Zhou X, et al.Targeting tumor-associated macrophages in head and neck squamous cell carcinoma[J]. Oral Oncol, 2020, 106: 104723-104731.
[5] Junttila MR, de Sauvage FJ. Influence of tumour micro-environment heterogeneity on therapeutic response[J]. Nature, 2013, 501(7467): 346-354.
[6] Mhaidly R, Mechta-Grigoriou F.Fibroblast heterogeneity in tumor micro-environment: role in immunosuppression and new therapies[J]. Semin Immunol, 2020, 48: 101417-101429.
[7] Kalluri R, Zeisberg M.Fibroblasts in cancer[J]. Nat Rev Cancer, 2006, 6(5): 392-401.
[8] Nurmik M, Ullmann P, Rodriguez F, et al.In search of definitions: cancer-associated fibroblasts and their markers[J]. Int J Cancer, 2020, 146(4): 895-905.
[9] Petitprez F, Meylan M, de Reyniès A, et al. The tumor microenvironment in the response to immune checkpoint blockade therapies[J]. Front Immunol, 2020, 11: 784-794.
[10] Jochems C, Schlom J.Tumor-infiltrating immune cells and prognosis: the potential link between conventional cancer therapy and immunity[J]. Exp Biol Med (Maywood), 2011, 236(5): 567-579.
[11] Kopp F, Mendell JT.Functional classification and experimental dissection of long noncoding RNAs[J]. Cell, 2018, 172(3): 393-407.
[12] Wang KC, Chang HY.Molecular mechanisms of long noncoding RNAs[J]. Mol Cell, 2011,43(6): 904-914.
[13] Zhou M, Zhang Z, Bao S, et al. Computational recognition of lncRNA signature of tumor-infiltrating B lymphocytes with potential implications in prognosis and immunotherapy of bladder cancer[J]. Brief Bioinform, 2021, 22(3): bbaa047-bbaa059.
[14] Li R, Li F, Wang Y, et al. A three-long non-coding RNA signature that predicts tongue squamous cell carcinoma prognosis[J]. Oral Dis, 2021 Jul 28.
[Online ahead of print].
[15] Seliger B, Massa C, Yang B, et al.Immune escape mechanisms and their clinical relevance in head and neck squamous cell carcinoma[J]. Int J Mol Sci, 2020, 21(19): 7032-7038.
[16] Postepska-Igielska A, Giwojna A, Gasri-Plotnitsky L, et al.LncRNA Khps1 regulates expression of the proto-oncogene SPHK1 via triplex-mediated changes in chromatin structure[J]. Mol Cell, 2015, 60(4): 626-636.
[17] Bridges MC, Daulagala AC, Kourtidis A.LNCcation: lncRNA localization and function[J]. J Cell Biol, 2021, 220(2): e202009045-e202009061.
[18] Ali T, Grote P.Beyond the RNA-dependent function of LncRNA genes[J]. Elife, 2020, 9: e60583-e60596.
[19] Yip CW, Sivaraman DM, Prabhu AV, et al.Functional annotation of lncRNA in high-throughput screening[J]. Essays Biochem, 2021, 65(4): 761-773.
[20] Wang L, Cho KB, Li Y, et al.Long Noncoding RNA (lncRNA)-mediated competing endogenous RNA networks provide novel potential biomarkers and therapeutic targets for colorectal cancer[J]. Int J Mol Sci, 2019, 20(22): 5758-5783.
[21] Fan CN, Ma L, Liu N.Systematic analysis of lncRNA-miRNA-mRNA competing endogenous RNA network identifies four-lncRNA signature as a prognostic biomarker for breast cancer[J]. J Transl Med, 2018, 16(1):264-275.
[22] Wang H, Huo X, Yang XR, et al.STAT3-mediated upregulation of lncRNA HOXD-AS1 as a ceRNA facilitates liver cancer metastasis by regulating SOX4[J]. Mol Cancer, 2017, 16(1): 136-150.
[23] Han C, Li H, Ma Z, et al.MIR99AHG is a noncoding tumor suppressor gene in lung adenocarcinoma[J]. Cell Death Dis, 2021, 12(5): 424-440.
[24] Mao X, Xu J, Wang W, et al.Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives[J]. Mol Cancer, 2021, 20(1):131-160.
[25] Fang Z, Meng Q, Xu J, et al.Signaling pathways in cancer-associated fibroblasts: recent advances and future perspectives[J]. Cancer Commun (Lond), 2023, 43(1): 3-41.
[26] 汪玉倩, 徐可, 詹月萍, 等. 肿瘤相关成纤维细胞及其标记物的研究现状[J].中国临床药理学杂志, 2022,37(17):2094-2097.
Wang YQ, Xu K, Zhan YP, et al.Research status of cancer-associated fibroblasts and their markers[J]. The Chinese Journal of Clinical Pharmacology, 2022, 37(17): 2094-2097
[27] Paulsson J, Micke P.Prognostic relevance of cancer-associated fibroblasts in human cancer[J]. Semin Cancer Biol, 2014, 25: 61-68.
[28] Wen S, Hou Y, Fu L, et al.Cancer-associated fibroblast (CAF)-derived IL32 promotes breast cancer cell invasion and metastasis via integrin β3-p38 MAPK signalling[J]. Cancer Lett, 2019, 442: 320-332.
[29] Desbois M, Wang Y.Cancer-associated fibroblasts: key players in shaping the tumor immune microenvironment[J]. Immunol Rev, 2021, 302(1): 241-258.
[30] Vered M, Dayan D, Yahalom R, et al.Cancer-associated fibroblasts and epithelial-mesenchymal transition in metastatic oral tongue squamous cell carcinoma[J]. Int J Cancer, 2010, 127(6): 1356-1362.
[31] Garaud S, Buisseret L, Solinas C, et al.Tumor infiltrating B-cells signal functional humoral immune responses in breast cancer[J]. JCI Insight, 2019, 5(18): e129641-e129660.
[32] Turley SJ, Cremasco V, Astarita JL.Immunological hallmarks of stromal cells in the tumour microenvironment[J]. Nat Rev Immunol, 2015, 15(11): 669-682.
[33] Thomas DA, Massagué J.TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance[J]. Cancer Cell, 2005, 8(5): 369-380.
[34] Chen X, Song E.Turning foes to friends: targeting cancer-associated fibroblasts[J]. Nat Rev Drug Discov, 2019, 18(2):99-115.

肿瘤相关成纤维细胞对头颈部鳞状细胞癌肿瘤浸润免疫细胞的调控作用及机制探讨

The regulation and mechanism of cancer-associated fibroblasts on tumor-infiltrating immune cells in head and neck squamous cell carcinoma

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