免疫检查点抑制剂在子宫内膜癌中的治疗与新进展
Treatment of Immune Checkpoint Inhibitors in Endometrial Cancer and New Advances
摘要: 近年来，随着医学领域在人体免疫方面进行越来越多的研究，免疫疗法在实体肿瘤中的治疗取得了良好的疗效。由于子宫内膜癌(Endometrialcancer, EC)中存在不同的分子亚型和免疫失调，免疫检查点阻断已被探索作为一种新的治疗机制。本文总结了现有的临床数据，以及正在进行和计划中的临床试验，就免疫检查点抑制剂(immune checkpoint inhibitor, ICI)在子宫内膜癌中的应用现状及联合治疗、局限性进行了综述，并展望了未来最有希望的研究方向。
Abstract: In recent years, as the medical field has conducted more and more research in human immunity, immunotherapy has achieved good efficacy in the treatment of solid tumors. Due to the presence of different molecular subtypes and immune dysregulation in endometrial cancer (EC), immune checkpoint blockade has been explored as a new therapeutic mechanism. In this article, we sum-marize the available clinical data, as well as ongoing and planned clinical trials, and review the cur-rent status of immune checkpoint inhibitor (ICI) use in endometrial cancer and its combination therapy, limitations, and look at the most promising future research directions.
文章引用：王艳婷, 魏梦凡, 赵红. 免疫检查点抑制剂在子宫内膜癌中的治疗与新进展[J]. 临床医学进展, 2023, 13(8): 12369-12377. https://doi.org/10.12677/ACM.2023.1381734

参考文献

[1] Konstantinopoulos, P.A., Liu, J.F., Barry, W.T., Krasner, C.N., Buss, M.K., Birrer, M.J., et al. (2017) Phase 2, Two-Group, Two-Stage, Open-Label Study of Avelumab in Patients with Microsatellite Stable, Microsatellite Instable and POLE-Mutated Recurrent or Persistent Endometrial Cancer. Journal of Clinical Oncology, 35, Article ID: TPS5615. [Google Scholar] [CrossRef] 
[2] Morice, P., Leary, A., Creutzberg, C., Abu-Rustum, N. and Darai, E. (2016) Endometrial Cancer. The Lancet Journal, 387, 1094-1108. [Google Scholar] [CrossRef] 
[3] Arthur, R.S., Kabat, G.C., Kim, M.Y., et al. (2019) Meta-bolic Syndrome and Risk of Endometrial Cancer in Postmenopausal Women: A Prospective Study. Cancer Causes Con-trol, 30, 355-363. [Google Scholar] [CrossRef] [PubMed]
[4] Friberg, E., Orsini, .N, Mantzoros, C.S. and Wolk, A. (2007) Diabetes Mellitus and Risk of Endometrial Cancer: A Meta-Analysis. Diabetologia, 50, 1365-1374. [Google Scholar] [CrossRef] [PubMed]
[5] Bokhman, J.V. (1983) Two Pathogenetic Types of Endometrial Carcinoma. Gynecologic Oncology, 15, 10-17. [Google Scholar] [CrossRef] [PubMed]
[6] Musacchio, L., Boccia, S.M., Caruso, G., et al. (2020) Im-mune Checkpoint Inhibitors: A Promising Choice for Endometrial Cancer Patients? Journal of Clinical Medicine, 9, Arti-cle No. 1721. [Google Scholar] [CrossRef] [PubMed]
[7] Wilczyński, M., Danielska, J. and Wilczyński, J. (2016) An Update of the Classical Bokhman’s Dualistic Model of Endometrial Cancer. Przegląd Menopauzalny, 15, 63-68. [Google Scholar] [CrossRef] [PubMed]
[8] Liu, Y.L. and Zamarin, D. (2018) Combination Immune Checkpoint Blockade Strategies to Maximize Immune Response in Gynecological Cancers. Current Oncology Reports, 20, Article No. 94. [Google Scholar] [CrossRef] [PubMed]
[9] Brooks, R.A., Fleming, G.F., Lastra, R.R., et al. (2019) Current Recommendations and Recent Progress in Endometrial Cancer. CA: A Cancer Journal for Clinicians, 69, 258-279. [Google Scholar] [CrossRef] [PubMed]
[10] 周琦, 吴小华, 刘继红, 李力, 朱笕青, 白萍, 盛修贵. 子宫内膜癌诊断与治疗指南(第四版) [J]. 中国实用妇科与产科杂志, 2018, 34(8): 880-886.
[11] Green, A.K., Feinberg, J. and Makker, V. (2020) A Review of Immune Checkpoint Blockade Therapy in Endometrial Cancer. American Society of Clinical Oncology Educational Book, 40, 238-244. [Google Scholar] [CrossRef] 
[12] Smyth, M.J., Ngiow, S.F., Ribas, A. and Teng, M.W. (2016) Combi-nation Cancer Immunotherapies Tailored to the Tumour Microenvironment. Nature Reviews Clinical Oncology, 13, 143-158. [Google Scholar] [CrossRef] [PubMed]
[13] Hanahan, D. and Weinberg, R.A. (2011) Hallmarks of Cancer: The Next Generation. Cell, 144, 646-674. [Google Scholar] [CrossRef] [PubMed]
[14] Longoria, T.C. and Eskander, R.N. (2015) Immunotherapy in En-dometrial Cancer—An Evolving Therapeutic Paradigm. Gynecologic Oncology Research and Practice, 2, Article No. 11. [Google Scholar] [CrossRef] [PubMed]
[15] Keir, M.E., Butte, M.J., Freeman, G.J. and Sharpe, A.H. (2008) PD-1 and Its Ligands in Tolerance and Immunity. Annual Review of Immunology, 26, 677-704. [Google Scholar] [CrossRef] [PubMed]
[16] Wu, Y., Chen, W., Xu, Z.P. and Gu, W. (2019) PD-L1 Distribution and Perspective for Cancer Immunotherapy-Blockade, Knockdown, or Inhibition. Frontiers in Im-munology, 10, Article 2022. [Google Scholar] [CrossRef] [PubMed]
[17] Freeman, G.J., Long, A.J., Iwai, Y., Bourque, K., Chernova, T., Nishimura, H., et al. (2000) Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation. Journal of Experimental Medicine, 192, 1027-1034. [Google Scholar] [CrossRef] [PubMed]
[18] Selby, M.J., et al. (2013) Anti-CTLA-4 Antibodies of IgG2a Isotype Enhance Antitumor Activity through Reduction of Intratumoral Regulatory T Cells. Cancer Immunology Research, 1, 32-42. [Google Scholar] [CrossRef] 
[19] Pardoll, D.M. (2012) The Blockade of Immune Checkpoints in Cancer Immunotherapy. Nature Reviews Cancer, 12, 252-264. [Google Scholar] [CrossRef] [PubMed]
[20] Parsa, A.T., et al. (2007) Loss of Tumour Suppressor PTEN Function Increases B7‑H1 Expression and Immunoresistance in Glioma. Nature Medicine, 13, 84-88. [Google Scholar] [CrossRef] [PubMed]
[21] Hamanishi, J., Mandai, M., Iwasaki, M., et al. (2007) Programmed Cell Death 1 Ligand 1 and Tumor-Infiltrating CD8+ T Lymphocytes Are Prognostic Factors of Hu-man Ovarian Cancer. Proceedings of the National Academy of Sciences of the United States of America, 104, 3360-3365. [Google Scholar] [CrossRef] [PubMed]
[22] Okazaki, T. and Honjo, T. (2007) PD-1 and PD-1 Ligands: From Discovery to Clinical Application. International Immunology, 19, 813-824. [Google Scholar] [CrossRef] [PubMed]
[23] 许标波, 贺毅憬, 王韦力, 等. 肿瘤免疫检查点抑制剂临床治疗的研究进展[J]. 中国临床药理学与治疗学, 2016, 21(2): 218-224.
[24] Herzog, T.J., Arguello, D., Reddy, S.K. and Gatalica, Z. (2015) PD-1, PDL1 Expression in 1599 Gynecological Cancers: Implications for Immunotherapy. Gyneco-logic Oncology, 137, 204-205. [Google Scholar] [CrossRef] 
[25] Marabelle, A., Le, D.T., Ascierto, P.A., Di Giacomo, A.M., De Jesus-Acosta, A., Delord, J.-P., Geva, R., Gottfried, M., Penel, N., Hansen, A.R., et al. (2020) Efficacy of Pembroli-zumab in Patients with Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results from the Phase II KEYNOTE-158 Study. Journal of Clinical Oncology, 38, 1-10. [Google Scholar] [CrossRef] 
[26] Fleming, G.F., Emens, L.A., Eder, J.P., Hamilton, E.P., Liu, J.F., Liu, B., Molinero, L., Fasso, M., O’Hear, C. and Braiteh, F.S. (2017) Clinical Activity, Safety and Biomarker Results from a Phase Ia Study of Atezolizumab (Atezo) in Advanced/Recurrent Endometrial Cancer (rEC). Journal of Clinical Oncology, 35, Article No. 5585. [Google Scholar] [CrossRef] 
[27] McDermott, D.F., Sosman, J.A., Sznol, M., Massard, C., Gordon, M.S., Hamid, O., et al. (2016) Atezolizumab, an Anti–Programmed Death-Ligand 1 Antibody, in Metastatic Renal Cell Carcinoma: Long-Term Safety, Clinical Activity, and Immune Correlates from a Phase Ia Study. Journal of Clinical Oncology, 34, 833-842. [Google Scholar] [CrossRef] 
[28] Zitvogel, L., Galluzzi, L., Smyth, M.J. and Kroemer, G. (2013) Mechanism of Action of Conventional and Targeted Anticancer Therapies: Reinstating Immunosurveillance. Immunity, 39, 74-88. [Google Scholar] [CrossRef] [PubMed]
[29] Colombo, N., Preti, E., Landoni, F., Carinelli, S., Colombo, A., Marini, C. and Sessa, C. (2013) Endometrial Cancer: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-up. Annals of Oncology, 24, vi33-vi38. [Google Scholar] [CrossRef] [PubMed]
[30] McMeekin, S., Dizon, D., Barter, J., Scambia, G., Manzyuk, L., Lis-yanskaya, A., Oaknin, A., Ringuette, S., Mukhopadhyay, P., Rosenberg, J., et al. (2015) Phase III Randomized Trial of Second-Line Ixabepilone versus Paclitaxel or Doxorubicin in Women with Advanced Endometrial Cancer. Gynecologic Oncology, 138, 18-23. [Google Scholar] [CrossRef] [PubMed]
[31] Labiano, S., Palazon, A. and Melero, I. (2015) Immune Response Regulation in the Tumor Microenvironment by Hypoxia. Seminars in Oncology, 42, 378-386. [Google Scholar] [CrossRef] [PubMed]
[32] Fukumura, D., Kloepper, J., Amoozgar, Z., Duda, D.G. and Jain, R.K. (2018) Enhancing Cancer Immunotherapy Using Antiangiogenics: Opportunities and Challenges. Nature Re-views Clinical Oncology, 15, 325-340. [Google Scholar] [CrossRef] [PubMed]
[33] Makker, V., Taylor, M.H., Aghajanian, C., Oaknin, A., Mier, J., Cohn, A.L., Romeo, M., Bratos, R., Brose, M.S., DiSimone, C., et al. (2020) Lenvatinib plus Pembrolizumab in Patients with Advanced Endometrial Cancer. Journal of Clinical Oncology, 38, 2981-2992. [Google Scholar] [CrossRef] 
[34] Demaria, S. and Formenti, S.C. (2012) Radiation as an Immunological Adjuvant: Current Evidence on Dose and Fractionation. Frontiers in Oncology, 2, Article 153. [Google Scholar] [CrossRef] [PubMed]
[35] Sharabi, A.B., Lim, M., DeWeese, T.L. and Drake, C.G. (2015) Ra-diation and Checkpoint Blockade Immunotherapy: Radiosensitisation and Potential Mechanisms of Synergy. The Lancet Oncology, 16, e498-e509. [Google Scholar] [CrossRef] 
[36] Hallahan, D., Kuchibhotla, J. and Wyble, C. (1996) Cell Ad-hesion Molecules Mediate Radiation-Induced Leukocyte Adhesion to the Vascular Endothelium. Cancer Research, 56, 5150-5155.
[37] Tuyaerts, S., Van Nuffel, A.M.T., Naert, E., Van Dam, P.A., Vuylsteke, P., De Caluwé, A., Aspeslagh, S., Dirix, P., Lippens, L., De Jaeghere, E., et al. (2019) PRIMMO Study Protocol: A Phase II Study Combining PD-1 Blockade, Radiation and Immunomodulation to Tackle Cervical and Uterine Cancer. BMC Cancer, 19, Article No. 506. [Google Scholar] [CrossRef] [PubMed]
[38] Kato, Y., Tabata, K., Hori, Y., Tachino, S., Okamoto, K. and Matsui, J. (2015) Abstract A92: Effects of Lenvatinib on Tumor-Associated Macrophages Enhance Antitumor Activity of PD-1 Signal Inhibitors. Molecular Cancer Therapeutics, 14, Article No. A92. [Google Scholar] [CrossRef] 
[39] Michot, J.M., Bigenwald, C., Champiat, S., Collins, M., Carbonnel, F., Postel-Vinay, S., Berdelou, A., Varga, A., Bahleda, R., Hollebecque, A., et al. (2016) Immune-Related Adverse Events with Immune Checkpoint Blockade: A Comprehensive Review. European Journal of Cancer, 378, 158-168. [Google Scholar] [CrossRef] [PubMed]
[40] Kumar, V., Chaudhary, N., Garg, M., Floudas, C.S., Soni, P. and Chandra, A.B. (2017) Current Diagnosis and Management of Immune Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitor Therapy. Frontiers in Pharmacology, 8, Article 49. [Google Scholar] [CrossRef] [PubMed]
[41] Postow, M. and Wolchok, J. (2016) Toxicities Associated with Checkpoint Inhibitor Immunotherapy. In: Post, T.W., Ed., UpToDate, UpToDate Inc., Waltham.
[42] Weber, J.S. (2012) Practical Management of Immune Related Adverse Events from Immune Checkpoint Protein Antibodies for the Oncolo-gist. American Society of Clinical Oncology Educational Book, 32, 174-177. [Google Scholar] [CrossRef] 
[43] Minor, D., Chin, K. and Kashani-Sabet, M. (2009) Inflixi-mab in the Treatment of Anti-CTLA4 Antibody (Ipilimumab) Induced Immune-Related Colitis. Cancer Biotherapy & Radiopharmaceuticals, 24, 321-325. [Google Scholar] [CrossRef] [PubMed]
[44] Bagchi, S., Yuan, R. and Engleman, E.G. (2021) Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance. Annual Review of Pathology: Mechanisms of Disease, 16, 223-249. [Google Scholar] [CrossRef] [PubMed]
[45] Saglam, O. and Conejo-Garcia, J. (2018) PD-1/PD-L1 Immune Checkpoint Inhibitors in Advanced Cervical Cancer. Integrative Cancer Science and Therapeutics, 5. [Google Scholar] [CrossRef] 
[46] Lao, Y., Shen, D., Zhang, W., He, R. and Jiang, M. (2022) Immune Checkpoint Inhibitors in Cancer Therapy—How to Overcome Drug Resistance? Cancers, 14, Article No. 3575. [Google Scholar] [CrossRef] [PubMed]
[47] Ishizuka, J.J., Manguso, R.T., Cheruiyot, C.K., et al. (2019) Loss of ADAR1 in Tumours Overcomes Resistance to Immune Checkpoint Blockade. Nature, 565, 43-48. [Google Scholar] [CrossRef] [PubMed]
[48] Ryan, N.A.J., Glaire, M.A., Blake, D., Cabrera-Dandy, M., Evans, D.G. and Crosbie, E.J. (2019) The Proportion of Endometrial Cancers Associated with Lynch Syndrome: A Systematic Review of the Literature and Meta-Analysis. Genetics in Medicine, 21, 2167-2180. [Google Scholar] [CrossRef] [PubMed]
[49] Crosbie, E.J., Ryan, N.A., Arends, M.J., Bosse, T., Burn, J., Cornes, J.M., Crawford, R., Eccles, D., Frayling, I.M., Ghaem-Maghami, S., et al. (2019) The Manchester International Consensus Group Recommendations for the Management of Gynecological Cancers in Lynch Syndrome. Genetics in Medicine, 21, 2390-2400. [Google Scholar] [CrossRef] [PubMed]

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