宫颈癌T细胞免疫应答与治疗进展
Cervical Cancer T-Cell Immune Response and Therapeutic Progress
DOI: 10.12677/ACM.2024.141045, PDF,   
作者: 周润生：济宁医学院临床医学院，山东 济宁；彭存旭*：济宁医学院附属医院妇科，山东 济宁
关键词: 宫颈癌；人乳头瘤病毒(HPV)；T细胞免疫应答；免疫检查点抑制剂；Cervical Cancer； Human Papillomavirus (HPV)； T-Cell Immune Response； Immune Checkpoint Inhibitors
摘要: 宫颈癌是全球女性常见的恶性肿瘤之一，与持续的高危型人乳头瘤病毒(HPV)感染密切相关。本文综述了宫颈癌的病理机制、T细胞免疫应答的作用与挑战，以及免疫检查点抑制剂(ICIs)在宫颈癌治疗中的应用和缺陷。研究表明，有效的T细胞免疫反应对于控制HPV感染和防止癌症的发展至关重要。然而，HPV蛋白(E6、E7、E5)通过干扰干扰素产生、降低T细胞活性和浸润，以及抑制抗原呈递系统，促进了免疫逃逸。因此，本文探讨了PD-1/PD-L1和CTLA-4免疫检查点在宫颈癌免疫应答中的关键作用，强调了TIM-3蛋白在表观遗传调控中的作用以及与宫颈癌预后的相关性。此外，本文还回顾了ICIs在宫颈癌治疗中的应用，包括单药疗法和双特异性抗体(BsAbs)的组合疗法，以及与之相关的不良反应和管理策略。这些发现揭示了宫颈癌治疗的新方向，并强调了在未来研究中探索个体化和精准医疗策略的重要性。
Abstract: Cervical cancer is one of the most common malignant tumors in women worldwide, and it is closely related to persistent high-risk human papillomavirus (HPV) infection. This article reviews the pathological mechanisms of cervical cancer, the role and challenges of T-cell immune responses, and the application and limitations of immune checkpoint inhibitors (ICIs) in the treatment of cervical cancer. Studies have shown that effective T-cell immune responses are crucial for controlling HPV infection and preventing the development of cancer. However, HPV proteins (E6, E7, E5) promote immune escape by interfering with interferon production, reducing T-cell activity and infiltration, and inhibiting the antigen presentation system. Therefore, this article explores the key roles of PD-1/PD-L1 and CTLA-4 immune checkpoints in the immune response of cervical cancer, empha-sizing the role of TIM-3 protein in epigenetic regulation and its correlation with the prognosis of cervical cancer. Additionally, this article reviews the application of ICIs in the treatment of cervical cancer, including monotherapy and the combination therapy with bispecific antibodies (BsAbs), as well as related adverse reactions and management strategies. These findings reveal new directions in the treatment of cervical cancer and emphasize the importance of exploring personalized and precision medical strategies in future research.
文章引用：周润生, 彭存旭. 宫颈癌T细胞免疫应答与治疗进展[J]. 临床医学进展, 2024, 14(1): 307-312. https://doi.org/10.12677/ACM.2024.141045

参考文献

[1] Siegel, R.L., Miller, K.D., Fuchs, H.E. and Jemal, A. (2022) Cancer Statistics, 2022. CA: A Cancer Journal for Clini-cians, 72, 7-33. [Google Scholar] [CrossRef] [PubMed]
[2] Okunade, K.S. (2020) Human Papillomavirus and Cervi-cal Cancer. Journal of Obstetrics and Gynaecology, 40, 602-608. [Google Scholar] [CrossRef] [PubMed]
[3] Murillo, R. and Ordóñez-Reyes, C. (2019) Human Papillo-mavirus (HPV) Vaccination: From Clinical Studies to Immunization Programs. International Journal of Gynecological Cancer, 29, 1317-1326. [Google Scholar] [CrossRef] [PubMed]
[4] Soto, D., Song, C. and Mclaughlin-Drubin, M.E. (2017) Epigenetic Alterations in Human Papillomavirus-Associated Cancers. Viruses, 9, Article No. 248. [Google Scholar] [CrossRef] [PubMed]
[5] Wherry, E.J. and Kurachi, M. (2015) Molecular and Cellular Insights into T Cell Exhaustion. Nature Reviews Immunology, 15, 486-499. [Google Scholar] [CrossRef] [PubMed]
[6] Shaikh, M.H., Bortnik, V., Mcmillan, N.A. and Idris, A. (2019) cGAS-STING Responses Are Dampened in High-Risk HPV Type 16 Positive Head and Neck Squamous Cell Carcinoma Cells. Microbial Pathogenesis, 132, 162-165. [Google Scholar] [CrossRef] [PubMed]
[7] Ronco, L.V., Karpova, A.Y., Vidal, M. and Howley, P.M. (1998) Human Papillomavirus 16 E6 Oncoprotein Binds to Interferon Regulatory Factor-3 and Inhibits Its Transcription-al Activity. Genes & Development, 12, 2061-2072. [Google Scholar] [CrossRef] [PubMed]
[8] Crusz, S.M. and Miller, R.E. (2020) Targeted Therapies in Gynaeco-logical Cancers. Histopathology, 76, 157-170. [Google Scholar] [CrossRef] [PubMed]
[9] Hemmat, N. and Baghi, H.B. (2018) Human Papillomavirus E5 Protein, the Undercover Culprit of Tumorigenesis. Infectious Agents and Cancer, 13, Article No. 31. [Google Scholar] [CrossRef] [PubMed]
[10] Li, X., Wang, R., Fan, P., Yao, X., Qin, L., Peng, Y., et al. (2019) A Comprehensive Analysis of Key Immune Checkpoint Receptors on Tumor-Infiltrating T Cells From Multiple Types of Cancer. Frontiers in Oncology, 9, Article No. 1066. [Google Scholar] [CrossRef] [PubMed]
[11] Dai, S., Zeng, H., Liu, Z., Jin, K., Jiang, W., Wang, Z., et al. (2021) Intratumoral CXCL13(+)CD8(+)T Cell Infiltration Determines Poor Clinical Outcomes and Immunoevasive Contexture in Patients with Clear Cell Renal Cell Carcinoma. The Journal for ImmunoTherapy of Cancer, 9, e001823. [Google Scholar] [CrossRef] [PubMed]
[12] Wu, Y., Chen, W., Xu, Z.P. and Gu, W. (2019) PD-L1 Distribution and Perspective for Cancer Immunotherapy—Blockade, Knockdown, or In-hibition. Frontiers in Immunology, 10, Article No. 2022. [Google Scholar] [CrossRef] [PubMed]
[13] Kraehenbuehl, L., Weng, C.H., Eghbali, S., Wolchok, J.D. and Merghoub, T. (2022) Enhancing Immunotherapy in Cancer by Targeting Emerging Immunomodulatory Pathways. Na-ture Reviews Clinical Oncology, 19, 37-50. [Google Scholar] [CrossRef] [PubMed]
[14] Allouch, S., Malki, A., Allouch, A., Gupta, I., Vranic, S. and Al Moustafa, A.E. (2020) High-Risk HPV Oncoproteins and PD-1/PD-L1 Interplay in Human Cervical Cancer: Recent Evidence and Future Directions. Frontiers in Oncology, 10, Article No. 914. [Google Scholar] [CrossRef] [PubMed]
[15] Liu, C., Lu, J., Tian, H., Du, W., Zhao, L., Feng, J., Yuan, D. and Li, Z. (2017) Increased Expression of PD‑L1 by the Human Papillomavirus 16 E7 Oncoprotein Inhibits Anticancer Immun-ity. Molecular Medicine Reports, 15, 1063-1070. [Google Scholar] [CrossRef] [PubMed]
[16] Wang, Y., Wang, C., Qiu, J., Qu, X., Peng, J., Lu, C., Zhang, M., Zhang, M., Qi, X., Li, G. and Hua, K. (2022) Targeting CD96 Overcomes PD-1 Blockade Resistance by Enhancing CD8+ TIL Function in Cervical Cancer. The Journal for ImmunoTherapy of Cancer, 10, e003667. [Google Scholar] [CrossRef] [PubMed]
[17] Podlesnykh, S.V., Abramova, K.E., Gordeeva, A., Khlebnikov, A.I. and Chapoval, A.I. (2021) Peptide Blocking CTLA-4 and B7-1 Interaction. Molecules, 26, 253. [Google Scholar] [CrossRef] [PubMed]
[18] Gao, H., Cai, H., Liu, J., Wang, X., Zheng, P., Devenport, M., Xu, T., Dou, F., Liu, Y. and Zhou, A. (2020) Structure of CTLA-4 Complexed with a pH-Sensitive Cancer Immuno-therapeutic Antibody. Cell Discovery, 6, Article No. 79. [Google Scholar] [CrossRef] [PubMed]
[19] Tie, Y., Tang, F., Wei, Y.Q. and Wei, X.W. (2022) Immuno-suppressive Cells in Cancer: Mechanisms and Potential Therapeutic Targets. Journal of Hematology & Oncology, 15, Article No. 61. [Google Scholar] [CrossRef] [PubMed]
[20] Monney, L., Sabatos, C.A., Gaglia, J.L., Ryu, A., Waldner, H., Chernova, T., Manning, S., Greenfield, E.A., Coyle, A.J., Sobel, R.A., Freeman, G.J. and Kuchroo, V.K. (2002) Th1-Specific Cell Surface Protein Tim-3 Regulates Macrophage Activation and Severity of an Autoimmune Disease. Nature, 415, 536-541. [Google Scholar] [CrossRef] [PubMed]
[21] Zhao, L., Cheng, S., Fan, L., Zhang, B. and Xu, S. (2021) TIM-3: An Update on Immunotherapy. International Immunopharmacology, 99, Article ID: 107933. [Google Scholar] [CrossRef] [PubMed]
[22] Chen, Z., Dong, D., Zhu, Y., Pang, N. and Ding, J. (2021) The Role of Tim-3/Galectin-9 Pathway in T-Cell Function and Prognosis of Patients with Human Papilloma Virus-Associated Cervical Carcinoma. The FASEB Journal, 35, e21401. [Google Scholar] [CrossRef] 
[23] Maiorano, B.A., Maiorano, M.F.P., Ciardiello, D., Maglione, A., Orditura, M., Lorusso, D. and Maiello, E. (2022) Beyond Plati-num, ICIs in Metastatic Cervical Cancer: A Systematic Review. Cancers (Basel), 14, Article No. 5955. [Google Scholar] [CrossRef] [PubMed]
[24] Wu, X., Ji, J., Lou, H., Li, Y., Feng, M., Xu, N., Li, Y., et al. (2022) Efficacy and Safety of Cadonilimab, an Anti-PD-1/CTLA4 Bi-Specific Antibody, in Previously Treated Recurrent or Metastatic (R/M) Cervical Cancer: A Multicenter, Open-Label, Single-Arm, Phase II Trial (075). Gynecologic Oncology, 166, S47-S48. [Google Scholar] [CrossRef] 
[25] O’malley, D.M., Neffa, M., Monk, B.J., Melkadze, T., Huang, M., Kryzhanivska, A., et al. (2022) Dual PD-1 and CTLA-4 Checkpoint Blockade Using Balstili-mab and Zalifrelimab Combination as Second-Line Treatment for Advanced Cervical Cancer: An Open-Label Phase II Study. Journal of Clinical Oncology, 40, 762-771. [Google Scholar] [CrossRef] [PubMed]
[26] Darnell, E.P., Mooradian, M.J., Baruch, E.N., Yilmaz, M. and Reynolds, K.L. (2020) Immune-Related Adverse Events (irAEs): Diagnosis, Management, and Clinical Pearls. Current Oncology Reports, 22, Article No. 39. [Google Scholar] [CrossRef] [PubMed]
[27] Wang, M., Ma, X., Guo, L. and Xia, F. (2017) Safety and Effi-cacy Profile of Pembrolizumab in Solid Cancer: Pooled Reanalysis Based on Randomized Controlled Trials. Drug De-sign, Development and Therapy, 11, 2851-2860. [Google Scholar] [CrossRef] 

为你推荐