HBV相关肝癌的CD8+T细胞抗肿瘤免疫机制研究进展
Research Progress on Anti-Tumor Immune Mechanism of CD8+T Cells in HBV-Related Hepatocellular Carcinoma
DOI: 10.12677/ACM.2021.115338, PDF,   
作者: 任丹丹*, 马金鑫#:延安大学附属医院,陕西 延安
关键词: 乙型肝炎病毒肝细胞癌CD8+T细胞Hepatitis B Virus Hepatocellular Carcinoma CD8+T Cell
摘要: 乙型肝炎病毒相关的肝细胞癌(HBV-HCC)通常被认为是与暴露于HBV和肿瘤抗原引发的慢性炎症相关的炎症相关的癌症。目前主要的治疗方案包括肝切除、肝移植、局部消融以及索拉菲尼化疗等方案。免疫治疗是一种新的治疗策略,通过增强机体自然免疫反应来治疗HBV-HCC,目前针对PD-1或CTLA-4的检查点阻断疗法已经在HCC患者中显示出初步的疗效。由于CD8+细胞毒性T淋巴细胞(CTLs)的产生在抗肿瘤免疫反应中起着重要作用,所以进一步探索HBV相关肝癌的CD8+T细胞抗肿瘤免疫机制非常必要。由于HBV相关肝癌的CD8+T细胞对HCC的免疫反应主要由病毒载量、肿瘤的抗原性以及癌症组织的微环境之间的平衡决定,本文将从HBV病毒载量、肿瘤抗原性以及肿瘤微环境三方面进行综述。
Abstract: Hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) is generally considered to be associated with chronic inflammation associated with exposure to HBV and tumor antigens. At present, the main treatment options include hepatectomy, liver transplantation, local ablation and sorafinib chemotherapy. Immunotherapy is a new treatment strategy to treat HBV-HCC, by enhancing the body’s natural immune response. At present, checkpoint blocking therapy for PD-1 or CTLA-4 has shown a preliminary effect in patients with HCC. Since the production of CD8+ cytotoxic T lymphocyte (CTLs) plays an important role in anti-tumor immune response, it is necessary to further explore the anti-tumor immune mechanism of CD8+T cells in HBV-related hepatocellular carcinoma. Since the immune response of CD8+T cells of HBV-related hepatocellular carcinoma to HCC is mainly determined by the balance among viral load, tumor antigenicity and cancer tissue microenvironment, this article will review the HBV viral load, tumor antigenicity and tumor microenvironment.
文章引用:任丹丹, 马金鑫. HBV相关肝癌的CD8+T细胞抗肿瘤免疫机制研究进展[J]. 临床医学进展, 2021, 11(5): 2347-2354. https://doi.org/10.12677/ACM.2021.115338

参考文献

[1] Bray, F., Ferlay, J., Soerjomataram, I., et al. (2018) Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 68, 394-424. [Google Scholar] [CrossRef] [PubMed]
[2] Siegel, R.L., Miller, K.D. and Jemal, A. (2016) Cancer Statistics, 2016. CA: A Cancer Journal for Clinicians, 66, 7-30. [Google Scholar] [CrossRef] [PubMed]
[3] Xie, Y.H. (2017) Hepatitis B Virus-Associated Hepatocellular Carcinoma. Advances in Experimental Medicine and Biology, 1018, 11-21. [Google Scholar] [CrossRef] [PubMed]
[4] Zhu, R.X., Seto, W.K., Lai, C.L., et al. (2016) Epidemiology of Hepatocellular Carcinoma in the Asia-Pacific Region. Gut and Liver, 10, 332-339. [Google Scholar] [CrossRef] [PubMed]
[5] Chen, Y.Y. and Tian, Z.G. (2019) HBV-Induced Immune Imbalance in the Development of HCC. Frontiers in Immunology, 10, 2048. [Google Scholar] [CrossRef] [PubMed]
[6] Wang, X.C., He, Q.F., Shen, H.Y., et al. (2019) Genetic and Phenotypic Difference in CD8 T Cell Exhaustion between Chronic Hepatitis B Infection and Hepatocellular Carcinoma. Journal of Medical Genetics, 56, 18-21. [Google Scholar] [CrossRef] [PubMed]
[7] Li, Z.L., Chen, G., Cai, Z.X., et al. (2019) Genomic and Transcriptional Profiling of Tumor Infiltrated CD8 T Cells Revealed Functional Heterogeneity of Antitumor Immunity in Hepatocellular Carcinoma. Oncoimmunology, 8, e1538436. [Google Scholar] [CrossRef
[8] Witjes, C.D., Ijzermans, J.N., Van Der Eijk, A.A., et al. (2011) Quantitative HBV DNA and AST Are Strong Predictors for Survival after HCC Detection in Chronic HBV Patients. Netherlands Journal of Medicine, 69, 508-513.
[9] Huang, S.Y., Xia, Y., Lei, Z.Q., et al. (2017) Antiviral Therapy Inhibits Viral Reactivation and Improves Survival after Repeat Hepatectomy for Hepatitis B Virus-Related Recurrent Hepatocellular Carcinoma. Journal of the American College of Surgeons, 224, 283-293.e4. [Google Scholar] [CrossRef] [PubMed]
[10] Tan, A.T. and Schreiber, S. (2020) Adoptive T-Cell Therapy for HBV-Associated HCC and HBV Infection. Antiviral Research, 176, Article ID: 104748. [Google Scholar] [CrossRef] [PubMed]
[11] Gehring, A.J., Ho, Z.Z., Tan, A.T., et al. (2009) Profile of Tumor Antigen-Specific CD8 T Cells in Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma. Gastroenterology, 137, 682-690. [Google Scholar] [CrossRef] [PubMed]
[12] Inada, Y., Mizukoshi, E., Seike, T., et al. (2019) Characteristics of Immune Response to Tumor-Associated Antigens and Immune Cell Profile in Patients with Hepatocellular Carcinoma. Hepatology, 69, 653-665. [Google Scholar] [CrossRef] [PubMed]
[13] Yang, H.Y., Sun, L.J., Guan, A., et al. (2021) Unique TP53 Neoantigen and the Immune Microenvironment in Long- Term Survivors of Hepatocellular Carcinoma. Cancer Immunology, Immunotherapy, 70, 667-677. [Google Scholar] [CrossRef] [PubMed]
[14] Rong, Y.H., Dong, Z., Hong, Z.X., et al. (2017) Reactivity toward Bifidobacterium longum and Enterococcus hirae Demonstrate Robust CD8 T Cell Response and Better Prognosis in HBV-Related Hepatocellular Carcinoma. Experimental Cell Research, 358, 352-359. [Google Scholar] [CrossRef] [PubMed]
[15] Donisi, C., Puzzoni, M., Ziranu, et al. (2020) Immune Checkpoint Inhibitors in the Treatment of HCC. Frontiers in Oncology, 10, Article ID: 601240. [Google Scholar] [CrossRef] [PubMed]
[16] Elkhoueiry, A.B., Sangro, B., Yau, T., et al. (2017) Nivolumab in Patients with Advanced Hepatocellular Carcinoma (CheckMate 040): An Open-Label, Non-Comparative, Phase 1/2 Dose Escalation and Expansion Trial. The Lancet, 389, 2492-2502. [Google Scholar] [CrossRef
[17] Duffy, A.G., Uiahannan, S.V., Makorova, R.O., et al. (2017) Tremelimumab in Combination with Ablation in Patients with Advanced Hepatocellular Carcinoma. Journal of Hepatology, 66, 545-551. [Google Scholar] [CrossRef] [PubMed]
[18] Liu, X.L., Li, M.G., Wang, X.H., et al. (2019) PD-1+ TIGIT+ CD8+ T Cells Are Associated with Pathogenesis and Progression of Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma. Cancer Immunology, Immunotherapy, 68, 2041-2054. [Google Scholar] [CrossRef] [PubMed]
[19] Liu, F.R., Zeng, G.C., Zhou, S.T., et al. (2018) Blocking Tim-3 or/and PD-1 Reverses Dysfunction of Tumor-Infil- trating Lymphocytes in HBV-Related Hepatocellular Carcinoma. Bulletin du Cancer, 105, 493-501. [Google Scholar] [CrossRef] [PubMed]
[20] Saeidi, A., Zandi, K., Cheok, Y.Y., et al. (2018) T-Cell Exhaustion in Chronic Infections: Reversing the State of Exhaustion and Reinvigorating Optimal Protective Immune Responses. Frontiers in Immunology, 9, 2569. [Google Scholar] [CrossRef] [PubMed]
[21] Otano, I., Escors, D., Schurich, A. et al. (2018) Molecular Recalibration of PD-1+ Antigen-Specific T Cells from Blood and Liver. Molecular Therapy, 26, 2553-2566. [Google Scholar] [CrossRef] [PubMed]
[22] Lim, C.J., Lee, Y.H., Pan, L., et al. (2019) Multidimensional Analyses Reveal Distinct Immune Microenvironment in Hepatitis B Virus-Related Hepatocellular Carcinoma. Gut, 68, 916-927. [Google Scholar] [CrossRef] [PubMed]
[23] Trehanpati, N. and Vyas, A.K. (2017) Immune Regulation by T Regulatory Cells in Hepatitis B Virus-Related Inflammation and Cancer. Scandinavian Journal of Immunology, 85, 175-181. [Google Scholar] [CrossRef] [PubMed]
[24] Song, G.H., Shi, Y., Zhang, M.Y., et al. (2020) Global Immune Characterization of HBV/HCV-Related Hepatocellular Carcinoma Identifies Macrophage and T-Cell Subsets Associated with Disease Progression. Cell Discovery, 6, 90. [Google Scholar] [CrossRef
[25] Li, T.Y., Zhang, X.Y., Lv, Z., et al. (2020) Increased Expression of Myeloid-Derived Suppressor Cells in Patients with HBV-Related Hepatocellular Carcinoma. BioMed Research International, 2020, Article ID: 6527192. [Google Scholar] [CrossRef] [PubMed]
[26] Hsiao, Y.W., Chiu, L.T., Chen, C.H., et al. (2019) Tumor-Infiltrating Leukocyte Composition and Prognostic Power in Hepatitis B- and Hepatitis C-Related Hepatocellular Carcinomas. Genes (Basel), 10, 630. [Google Scholar] [CrossRef] [PubMed]
[27] Shi, J.X., Wang, F.M., et al. (2020) Interleukin 22 Is Related to Development and Poor Prognosis of Hepatocellular Carcinoma. Clinics and Research in Hepatology and Gastroenterology, 44, 855-864. [Google Scholar] [CrossRef] [PubMed]
[28] Nishida, N. and Kudo, M. (2017) Immunological Microenvironment of Hepatocellular Carcinoma and Its Clinical Implication. Oncology, 92, 40-49. [Google Scholar] [CrossRef] [PubMed]
[29] Wang, Y.G., Zheng, D.H., Shi, M., et al. (2019) T Cell Dysfunction in Chronic Hepatitis B Infection and Liver Cancer: Evidence from Transcriptome Analysis. Journal of Medical Genetics, 56, 22-28. [Google Scholar] [CrossRef] [PubMed]
[30] Sanderson, S.M. and Locasale, J.W. (2018) Revisiting the Warburg Effect: Some Tumors Hold Their Breath. Cell Metabolism, 28, 669-670. [Google Scholar] [CrossRef] [PubMed]
[31] Tian, H.N., Zhu, X.Y., Lv, Y., et al. (2020) Glucometabolic Reprogramming in the Hepatocellular Carcinoma Microenvironment: Cause and Effect. Cancer Management and Research, 12, 5957-5974. [Google Scholar] [CrossRef
[32] Sharabi, K., Tavares, C.D.J., Rines, A.K., et al. (2015) Molecular Pathophysiology of Hepatic Glucose Production. Molecular Aspects of Medicine, 46, 21-33. [Google Scholar] [CrossRef] [PubMed]
[33] Bian, X.L., Chen, H.Z., Yang, P.B., et al. (2017) Nur77 Suppresses Hepatocellular Carcinoma via Switching Glucose Metabolism toward Gluconeogenesis through Attenuating Phosphoenolpyruvate Carboxykinase Sumoylation. Nature Communications, 8, Article No. 14420. [Google Scholar] [CrossRef] [PubMed]
[34] Singh, L., Aldosary, S., Saeedan, A.S., et al. (2018) Prolyl Hydroxylase 2: A Promising Target to Inhibit Hypoxia-Induced Cellular Metabolism in Cancer Cells. Drug Discovery Today, 23, 1873-1882. [Google Scholar] [CrossRef] [PubMed]
[35] Liu, Y.Y., Jiang, Y.Q., Zhang, M., et al. (2018) Modulating Hypoxia via Nanomaterials Chemistry for Efficient Treatment of Solid Tumors. Accounts of Chemical Research, 51, 2502-2511. [Google Scholar] [CrossRef] [PubMed]
[36] Yang, J., Jin, X., Yan, Y.Q., et al. (2017) Inhibiting Histone Deacetylases Suppresses Glucose Metabolism and Hepatocellular Carcinoma Growth by Restoring FBP1 Expression. Scientific Reports, 7, Article No. 43864. [Google Scholar] [CrossRef] [PubMed]
[37] Lu, Z.N., Tian, B. and Guo, X.L. (2017) Repositioning of Proton Pump Inhibitors in Cancer Therapy. Cancer Chemotherapy and Pharmacology, 80, 925-937. [Google Scholar] [CrossRef] [PubMed]
[38] Martinez, O.U.E., Ppeiris, P.M., Pestell, R.G., et al. (2017) Cancer Metabolism: A Therapeutic Perspective. Nature Reviews Clinical Oncology, 14, 11-31. [Google Scholar] [CrossRef] [PubMed]
[39] Fortunato, S., Bononi, G.C., et al. (2018) An Update on Patents Covering Agents That Interfere with the Cancer Glycolytic Cascade. ChemMedChem, 13, 2251-2265. [Google Scholar] [CrossRef] [PubMed]