胰腺癌是一种恶性程度高、病死率高的疾病。手术治疗仍是治疗胰腺癌的有效方法,但胰腺癌的症状通常较晚,就诊时大多数病人已经失去了手术机会,即使采取多种综合治疗方式仍不能有效改善患者总体生存率,故胰腺癌患者的预后差,死亡率高。免疫疗法是除手术、化疗、放疗、靶向治疗等以外的另一种重要的治疗方式,但免疫治疗在胰腺癌中收效甚微,这可能与胰腺癌独特的生物学行为及肿瘤微环境有关。通过阅读大量相关文献综述了胰腺癌的肿瘤免疫抑制微环境及免疫治疗的研究进展,包括检查点抑制剂、肿瘤的疫苗治疗、过继细胞治疗、溶瘤病毒等,提出了个体化和联合用药治疗胰腺癌的一些建议。
Pancreatic cancer is a disease with high malignancy and mortality. Surgical treatment is still an effective way to treat pancreatic cancer, but the symptoms of pancreatic cancer are usually late, and most patients have lost the opportunity for surgery when they are treated. Even if multiple comprehensive treatment methods are adopted, the overall survival rate of patients still cannot be effectively improved, so the prognosis of patients with pancreatic cancer is poor and the mortality rate is high. Immunotherapy is another important therapy besides surgery, chemotherapy, radiotherapy and targeted therapy. However, immunotherapy has little effect on pancreatic cancer, which may be related to the unique biological behavior and tumor microenvironment of pancreatic cancer. This paper reviews the progress of tumor immunosuppressive microenvironment and immunotherapy of pancreatic cancer, including checkpoint inhibitors, tumor vaccine therapy, adoptive cell therapy, oncolytic virus, etc., and puts forward some suggestions on individual and combination therapy for pancreatic cancer.
Pancreatic cancer is a disease with high malignancy and mortality. Surgical treatment is still an effective way to treat pancreatic cancer, but the symptoms of pancreatic cancer are usually late, and most patients have lost the opportunity for surgery when they are treated. Even if multiple comprehensive treatment methods are adopted, the overall survival rate of patients still cannot be effectively improved, so the prognosis of patients with pancreatic cancer is poor and the mortality rate is high. Immunotherapy is another important therapy besides surgery, chemotherapy, radiotherapy and targeted therapy. However, immunotherapy has little effect on pancreatic cancer, which may be related to the unique biological behavior and tumor microenvironment of pancreatic cancer. This paper reviews the progress of tumor immunosuppressive microenvironment and immunotherapy of pancreatic cancer, including checkpoint inhibitors, tumor vaccine therapy, adoptive cell therapy, oncolytic virus, etc., and puts forward some suggestions on individual and combination therapy for pancreatic cancer.
免疫应答通过表面受体协调细胞间的通信,介导免疫反应,并提供稳态机制减少慢性炎症导致的过度损伤,并且防止了自身免疫 [12]。免疫检查点和其他T细胞共抑制途径是一类主要的受体,作为一种免疫治疗靶点受到更多的关注。这类受体主要包括程序性死亡蛋白1 (Programmed death protein 1, PD-1)及其配体(Programmed death protein ligand 1, PD-L1)、细胞毒性T淋巴细胞抗原4 (Cytotoxic T lymphocyte antigen 4, CTLA4)、T细胞免疫球蛋白和含黏蛋白结构域3 (Tcell immunoglobulin and mucin domain-containing 3, TIM3)、吲哚胺2,3-双加氧酶(Indoleamine 2,3-dioxygenase, IDO)等。这些免疫抑制途径的识别导致了单克隆抗体的发展,以结合和阻断这些抑制配体或受体,增强潜在的抗肿瘤免疫活性 [13]。
郑荔文,刘长安. 胰腺癌免疫治疗研究进展Research Progress in Immunotherapy of Pancreatic Cancer[J]. 临床医学进展, 2022, 12(02): 1169-1177. https://doi.org/10.12677/ACM.2022.122170
参考文献ReferencesWu, J. and Cai, J. (2021) Dilemma and Challenge of Immunotherapy for Pancreatic Cancer. Digestive Diseases and Sciences, 66, 359-368. <br>https://doi.org/10.1007/s10620-020-06183-9Sunami, Y. and Kleeff, J. (2019) Immunotherapy of Pancreatic Cancer. Progress in Molecular Biology and Translational Science, 164, 189-216. <br>https://doi.org/10.1016/bs.pmbts.2019.03.006Banerjee, K., Kumar S, Ross, K.A., Gautam, S., Poelaert, B., Nasser, M.W., et al. (2018) Emerging Trends in the Immunotherapy of Pancreatic Cancer. Cancer Letters, 417, 35-46. <br>https://doi.org/10.1016/j.canlet.2017.12.012Batista, I. and Melo, S. (2019) Exosomes and the Future of Immunotherapy in Pancreatic Cancer. International Journal of Molecular Sciences, 20, Article No. 567. <br>https://doi.org/10.3390/ijms20030567Ren, B., Cui, M., Yang, G., Wang, H., Feng, M., You, L., et al. (2018) Tumor Microenvironment Participates in Metastasis of Pancreatic Cancer. Molecular Cancer, 17, Article No. 108. <br>https://doi.org/10.1186/s12943-018-0858-1Yao, W., Maitra, A. and Ying, H. (2020) Recent Insights into the Biology of Pancreatic Cancer. eBioMedicine, 53, Article ID: 102655. <br>https://doi.org/10.1016/j.ebiom.2020.102655Schizas, D., Charalampakis, N., Kole, C., Economopoulou, P., Koustas, E., Gkotsis, E., et al. (2020) Immunotherapy for Pancreatic Cancer: A 2020 Update. Cancer Treatment Reviews, 86, Article ID: 102016.
<br>https://doi.org/10.1016/j.ctrv.2020.102016Dougan, S.K. (2017) The Pancreatic Cancer Microenvironment. The Cancer Journal, 23, 321-325.
<br>https://doi.org/10.1097/PPO.0000000000000288叶辰, Zheng, L., 原春辉. 胰腺癌免疫微环境及免疫治疗的前景与展望[J]. 中华外科杂志, 2019, 57(1): 10-15.Li, J., Byrne, K.T., Yan, F., Yamazoe, T., Chen, Z., Baslan, T., et al. (2018) Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy. Immunity, 49, 178-193.E7.
<br>https://doi.org/10.1016/j.immuni.2018.06.006Leinwand, J. and Miller, G. (2020) Regulation and Modulation of Antitumor Immunity in Pancreatic Cancer. Nature Immunology, 21, 1152-1159. <br>https://doi.org/10.1038/s41590-020-0761-yMelero, I., Berman, D.M., Aznar, M.A., Korman, A.J., Pérez Gracia, J.L. and Haanen, J. (2015) Evolving Synergistic Combinations of Targeted immunotherapies To Combat Cancer. Nature Reviews Cancer, 15, 457-472.
<br>https://doi.org/10.1038/nrc3973Blair, A.B. and Zheng, L. (2017) Rational Combinations of Immunotherapy for Pancreatic Ductal Adenocarcinoma. Chinese Clinical Oncology, 6, Article No. 31. <br>https://doi.org/10.21037/cco.2017.06.04Brahmer, J.R., Tykodi, S.S., Chow, L.Q., Hwu, W.J., Topalian, S.L. and Hwu, P, (2012) Safety and Activity of Anti-PD-L1 Antibody in Patients with Advanced Cance. New England Journal of Medicine, 366, 2455-2465.
<br>https://doi.org/10.1056/NEJMoa1200694Camacho, L.H. (2015) CTLA-4 Blockade with Ipilimumab: Biology, Safety, Efficacy, and Future Considerations. Cancer Medicine, 4, 661-672. <br>https://doi.org/10.1002/cam4.371Skelton, R.A., Javed, A., Zheng, L. and He, J. (2017) Overcoming the Resistance of Pancreatic Cancer to Immune Checkpoint Inhibitors. Journal of Surgical Oncology, 116, 55-62. <br>https://doi.org/10.1002/jso.24642Witkiewicz, A., Williams, T.K., Cozzitorto, J., Durkan, B., Showalter, S.L. and Yeo, C.J. (2008) Expression of Indoleamine 2,3-Dioxygenase in Metastatic Pancreatic Ductal Adenocarcinoma Recruits Regulatory T Cells to Avoid Immune Detection. Journal of the American College of Surgeons, 206, 849-854.
<br>https://doi.org/10.1016/j.jamcollsurg.2007.12.014Manuel, E.R., Chen, J., D’Apuzzo, M., Lampa, M.G., Kaltcheva, T.I. and Thompson, C.B. (2015) Salmonella-Based Therapy Targeting Indoleamine 2,3-Dioxygenase Coupled with Enzymatic Depletion of Tumor Hyaluronan Induces Complete Regression of Aggressive Pancreatic Tumors. Cancer Immunology Research, 3, 1096-1107.
<br>https://doi.org/10.1158/2326-6066.CIR-14-0214Holmgaard, R.B., Zamarin, D., Munn, D.H., Wolchok, J.D. and Allison, J.P. (2013) Indoleamine 2,3-Dioxygenase Is a Critical Resistance Mechanism in Antitumor T Cell Immunotherapy Targeting CTLA-4. Journal of Experimental Medicine, 210, 1389-1402. <br>https://doi.org/10.1084/jem.20130066McCormick, K.A., Coveler, A.L., Rossi, G.R., Vahanian, N.N., Link, C. and Chiorean, E.G. (2015) Pancreatic Cancer: Update on Immunotherapies and Algenpantucel-L. Human Vaccines & Immunotherapeutics, 12, 563-575.
<br>https://doi.org/10.1080/21645515.2015.1093264Sahin, I.H., Askan, G., Hu, Z. and O’Reilly, E.M. (2017) Immunotherapy in Pancreatic Ductal Adenocarcinoma: An Emerging Entity? Annals of Oncology, 28, 2950-2961. <br>https://doi.org/10.1093/annonc/mdx503Li, M., Bharadwaj, U., Zhang, R., Zhang, S., Mu, H. and Fisher, W.E., et al. (2008) Mesothelin Is a Malignant Factor and Therapeutic Vaccine Target for Pancreatic Cancer. Molecular Cancer Therapeutics, 7, 286-296.
<br>https://doi.org/10.1158/1535-7163.MCT-07-0483Lepisto, A.J., Moser, A.J., Zeh, H., Lee, K., Bartlett, D., McKolanis, J.R., et al. (2008) A Phase I/II Study of a MUC1 Peptide Pulsed Autologous Dendritic Cell Vaccine as Adjuvant Therapy in Patients with Resected Pancreatic and Biliary Tumors. Cancer Therapy, 6, 955-964.Deguchi, T., Tanemura, M., Miyoshi, E., Nagano, H., Machida, T., Ohmura, Y., et al. (2010) Increased Immunogenicity of Tumor-Associated Antigen, Mucin 1, Engineered to Express Alpha-Gal Epitopes: A Novel Approach to Immunotherapy in Pancreatic Cancer. Cancer Research, 70, 5259-5269. <br>https://doi.org/10.1158/0008-5472.CAN-09-4313Bernhardt, S.L., Gjertsen, M.K., Trachsel, S., Møller, M., Eriksen, J.A., Meo, M., et al. (2006) Telomerase Peptide Vaccination of Patients with Non-Resectable Pancreatic Cancer: A Dose Escalating Phase I/II Study. British Journal of Cancer, 95, 1474-1482. <br>https://doi.org/10.1038/sj.bjc.6603437Wobser, M., Keikavoussi, P., Kunzmann, V., Weininger, M., Andersen, M.H. and Becker, J.C. (2006) Complete Remission of Liver Metastasis of Pancreatic Cancer under Vaccination with a HLA-A2 Restricted Peptide Derived from the Universal Tumor Antigen Surviving. Cancer Immunology, Immunotherapy, 55, 1294-1298.
<br>https://doi.org/10.1007/s00262-005-0102-xNishida, S., Koido, S., Takeda, Y., Homma, S., Komita, H., Takahara, A., et al. (2014) Wilms Tumor Gene (WT1) Peptide-Based Cancer Vaccine Combined with Gemcitabine for Patients with Advanced Pancreatic Cancer. Journal of Immunotherapy, 37, 105-114. <br>https://doi.org/10.1097/CJI.0000000000000020Yanagimoto, H., Shiomi, H., Satoi, S., Mine, T., Toyokawa, H., Yamamoto, T., et al. (2010) A Phase II Study of Personalized Peptide Vaccination Combined with Gemcitabine for Non-Resectable Pancreatic Cancer Patients. Oncology Reports, 24, 795-801. <br>https://doi.org/10.3892/or_00000923Laheru, D., Lutz, E., Burke, J., Biedrzycki, B., Solt, S. and Onners, B., et al. (2008) Allogeneic Granulocyte Macrophage Colony-Stimulating Factor-Secreting Tumor Immunotherapy alone or in Sequence with Cyclophosphamide for Metastatic Pancreatic Cancer: A Pilot Study of Safety, Feasibility, and Immune Activation. Clinical Cancer Research, 14, 1455-1463. <br>https://doi.org/10.1158/1078-0432.CCR-07-0371Le, D.T., Wang-Gillam, A., Picozzi, V., Greten, T.F., Crocenzi, T. and Springett, G., et al. (2015) Safety and Survival with GVAX Pancreas Prime and Listeria Monocytogenes-Expressing Mesothelin (CRS-207) Boost Vaccines for Metastatic Pancreatic Cancer. Journal of Clinical Oncology, 33, 1325-1333. <br>https://doi.org/10.1200/JCO.2014.57.4244Le, D.T., Lutz, E., Uram, J.N., Sugar, E.A., Onners, B., Solt, S., et al. (2013) Evaluation of Ipilimumab in Combination with Allogeneic Pancreatic Tumor Cells Transfected with a GM-CSF Gene in Previously Treated Pancreatic Cancer. Journal of Immunotherapy, 36, 382-389. <br>https://doi.org/10.1097/CJI.0b013e31829fb7a2Liu, J., Zhong, J.F., Zhang, X. and Zhang, C. (2017) Allogeneic CD19-CAR-T Cell Infusion after Allogeneic Hematopoietic Stem Cell Transplantation in B Cell Malignancies. Journal of Hematology & Oncology, 10, Article No. 35.
<br>https://doi.org/10.1186/s13045-017-0405-3Ali, A.I., Oliver, A.J., Samiei, T., Chan, J.D., Kershaw, M.H. and Slaney, C.Y. (2019) Genetic Redirection of T Cells for the Treatment of Pancreatic Cancer. Frontiers in Oncology, 9, Article No. 56.
<br>https://doi.org/10.3389/fonc.2019.00056Li, T., Li, H., Li, S., Xu, S., Zhang, W., Gao, H., et al. (2019) Research Progress and Design Optimization of CAR-T Therapy for Pancreatic Ductal Adenocarcinoma. Cancer Medicine, 8, 5223-5231. <br>https://doi.org/10.1002/cam4.2430Jiang, H., Shi, Z., Wang, P., Wang, C., Yang, L., Du, G., et al. (2019) Claudin18.2-Specific Chimeric Antigen Receptor Engineered T Cells for the Treatment of Gastric Cancer. Journal of the National Cancer Institute, 111, 409-418.
<br>https://doi.org/10.1093/jnci/djy134Chen, N., Li, X., Chintala, N.K., Tano, Z.E. and Adusumilli, P.S. (2018) Driving CARs on the Uneven Road of Antigen Heterogeneity in Solid Tumors. Current Opinion in Immunology, 51, 103-110.
<br>https://doi.org/10.1016/j.coi.2018.03.002Posey Jr., A.D., Schwab, R.D., Boesteanu, A.C., Steentoft, C., Mandel, U., Engels, B., et al (2016) Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma. Immunity, 44, 1444-1454. <br>https://doi.org/10.1016/j.immuni.2016.05.014Golubovskaya, V., Berahovich, R., Zhou, H., Xu, S., Harto, H., Li, L., et al. (2017) CD47-CAR-T Cells Effectively Kill Target Cancer Cells and Block Pancreatic Tumor Growth. Cancers, 9, Article No. 139.
<br>https://doi.org/10.3390/cancers9100139Raj, D., Yang, M.H., Rodgers, D., Hampton, E.N., Begum, J., Mustafa, A., et al. (2018) Switchable CAR-T Cells Mediate Remission in Metastatic Pancreatic Ductal Adenocarcinoma. Gut, 68, 1052-1064.
<br>https://doi.org/10.1136/gutjnl-2018-316595Sukumaran, S., Watanabe, N., Bajgain, P., Raja, K., Mohammed, S. and Fisher, W.E. (2018) Enhancing the Potency and Specificity of Engineered T Cells for Cancer Treatment. Cancer Discovery, 8, 972-987.
<br>https://doi.org/10.1158/2159-8290.CD-17-1298Jiang, J., Zhou, H., Ni, C., Hu, X., Mou, Y. and Huang, D, (2018) Immunotherapy in Pancreatic Cancer: New Hope or Mission Impossible? Cancer Letters, 445, 57-64. <br>https://doi.org/10.1016/j.canlet.2018.10.045Hecht, J.R., Bedford, R., Abbruzzese, J.L., Lahoti, S., Reid, T.R., Soetikno, R.M., et al. (2003) A Phase I/II trial of Intratumoral Endoscopic Ultrasound Injection of ONYX-015 with Intravenous Gemcitabine in Unresectable Pancreatic Carcinoma. Clinical Cancer Research, 9, 555-561.Noonan, A.M., Farren, M.R., Geyer, S.M., Huang, Y., Tahiri, S., Ahn, D., et al. (2016) Randomized Phase 2 Trial of the Oncolytic Virus Pelareorep (Reolysin) in Upfront Treatment of Metastatic Pancreatic Adenocarcinoma. Molecular Therapy, 24, 1150-1158. <br>https://doi.org/10.1038/mt.2016.66Hidalgo, M., Cascinu, S., Kleeff, J., Labianca, R., Löhr, J.M., Neoptolemos, J., et al. (2015) Addressing the Challenges of Pancreatic Cancer: Future Directions for Improving Outcomes. Pancreatology, 15, 8-18.
<br>https://doi.org/10.1016/j.pan.2014.10.001