黑素瘤免疫治疗的难点及对策

doi:10.35541/cjd.20201111

中华皮肤科杂志 ›› 2021, Vol. 54 ›› Issue (4): 313-317.doi: 10.35541/cjd.20201111

黑素瘤免疫治疗的难点及对策

沙姗姗¹ 李军² 陶娟¹

¹华中科技大学同济医学院附属协和医院皮肤科，武汉 430022；²华中科技大学同济医学院附属武汉市中心医院皮肤科 430014

收稿日期:2020-11-20 修回日期:2021-01-12 发布日期:2021-03-31
通讯作者: 陶娟 E-mail:tjhappy@126.com
基金资助:
国家自然科学基金;国家自然科学基金

Melanoma immunotherapy: difficulties and strategies

Sha Shanshan¹, Li Jun², Tao Juan¹

¹Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; ²Department of Dermatology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China

Received:2020-11-20 Revised:2021-01-12 Published:2021-03-31
Contact: Tao Juan E-mail:tjhappy@126.com
Supported by:
National Natural Science Foundation of China;National Natural Science Foundation of China

摘要/Abstract

摘要： 【摘要】黑素瘤是高度恶性的免疫原性肿瘤，尽管以免疫检查点抑制剂为代表的免疫治疗可显著提高转移性黑素瘤患者的生存率，但仍有近半数患者对免疫治疗产生耐受和抵抗，且免疫相关不良反应发生率高。本文聚焦目前黑素瘤免疫治疗存在的耐受、抵抗及免疫相关不良反应等关键难点，总结相应的对策与研究进展。通过干预黑素瘤免疫抑制性微环境、筛选精准的生物标记物及优化免疫治疗联合策略等能够帮助解决免疫治疗耐受和抵抗的问题，同时传统免疫治疗与纳米技术的结合也可大幅减少免疫相关不良反应的发生。未来，对肿瘤免疫微环境更为广泛和深入的研究将有助于探索黑素瘤免疫治疗的最佳方式。

关键词: 痣和黑素瘤, 免疫疗法, 生物制剂, 免疫耐受, 免疫相关不良反应, 生物标记物

Abstract: 【Abstract】 Melanoma is a highly malignant immunogenic tumor. Although immunotherapy represented by immune checkpoint inhibitors can markedly improve the survival rate of patients with metastatic melanoma, nearly half of patients are still tolerant or resistant to immunotherapy, with high incidence of immune-related adverse reactions. This review focuses on the key difficulties in tolerance, resistance and immune-related adverse reactions to current melanoma immunotherapy, and summarizes corresponding strategies and research advances. By intervening in the immunosuppressive microenvironment in melanoma, screening precise biomarkers, and optimizing immunotherapy-based combination strategies, the problem of tolerance and resistance to immunotherapy can be solved. Moreover, the combination of traditional immunotherapy and nanotechnology can also greatly reduce the occurrence of immune-related adverse reactions. In the future, more extensive and in-depth research on the tumor immune microenvironment will help to explore the best immunotherapy regimens for melanoma.

Key words: Nevi and melanomas, Immunotherapy, Biological agents, Immune tolerance, Immune-related adverse effects, Biomarkers

沙姗姗李军陶娟. 黑素瘤免疫治疗的难点及对策[J]. 中华皮肤科杂志, 2021,54(4):313-317. doi:10.35541/cjd.20201111

Sha Shanshan, Li Jun, Tao Juan. Melanoma immunotherapy: difficulties and strategies[J]. Chinese Journal of Dermatology, 2021, 54(4): 313-317.doi:10.35541/cjd.20201111

参考文献 45

［1］	Luke JJ, Flaherty KT, Ribas A, et al. Targeted agents and immunotherapies: optimizing outcomes in melanoma［J］. Nat Rev Clin Oncol, 2017,14（8）:463⁃482. doi: 10.1038/nrclinonc.2017. 43.
［2］	Jenkins RW, Fisher DE. Treatment of advanced melanoma in 2020 and beyond［J］. J Invest Dermatol, 2021,141（1）:23⁃31. doi: 10.1016/j.jid.2020.03.943.
［3］	Zhang Y, Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor⁃infiltrating immune cells and their therapeutic implications［J］. Cell Mol Immunol, 2020,17（8）:807⁃821. doi: 10.1038/s41423⁃020⁃0488⁃6.
［4］	Vujanovic L, Butterfield LH. Melanoma cancer vaccines and anti⁃tumor T cell responses［J］. J Cell Biochem, 2007,102（2）:301⁃310. doi: 10.1002/jcb.21473.
［5］	Davey RJ, van der Westhuizen A, Bowden NA. Metastatic melanoma treatment: combining old and new therapies［J］. Crit Rev Oncol Hematol, 2016,98:242⁃253. doi: 10.1016/j.critrevonc. 2015.11.011.
［6］	Hamid O, Ismail R, Puzanov I. Intratumoral immunotherapy⁃update 2019［J］. Oncologist, 2020,25（3）:e423⁃e438. doi: 10.1634/ theoncologist.2019⁃0438.
［7］	Rohaan MW, van den Berg JH, Kvistborg P, et al. Adoptive transfer of tumor⁃infiltrating lymphocytes in melanoma: a viable treatment option［J］. J Immunother Cancer, 2018,6（1）:102. doi: 10.1186/s40425⁃018⁃0391⁃1.
［8］	Seth R, Messersmith H, Kaur V, et al. Systemic therapy for melanoma: ASCO guideline［J］. J Clin Oncol, 2020,38（33）:3947⁃3970. doi: 10.1200/JCO.20.00198.
［9］	Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies［J］. Nat Rev Drug Discov, 2019,18（3）:197⁃218. doi: 10.1038/s41573⁃018⁃0007⁃y.
［10］	Ayers M, Nebozhyn M, Cristescu R, et al. Molecular profiling of cohorts of tumor samples to guide clinical development of pembrolizumab as monotherapy［J］. Clin Cancer Res, 2019,25（5）:1564⁃1573. doi: 10.1158/1078⁃0432.CCR⁃18⁃1316.
［11］	Hegde PS, Karanikas V, Evers S. The where, the when, and the how of immune monitoring for cancer immunotherapies in the era of checkpoint inhibition［J］. Clin Cancer Res, 2016,22（8）:1865⁃1874. doi: 10.1158/1078⁃0432.CCR⁃15⁃1507.
［12］	Mariathasan S, Turley SJ, Nickles D, et al. TGFβ attenuates tumour response to PD⁃L1 blockade by contributing to exclusion of T cells［J］. Nature, 2018,554（7693）:544⁃548. doi: 10.1038/nature25501.
［13］	Engblom C, Pfirschke C, Pittet MJ. The role of myeloid cells in cancer therapies［J］. Nat Rev Cancer, 2016,16（7）:447⁃462. doi: 10.1038/nrc.2016.54.
［14］	Hegde PS, Chen DS. Top 10 challenges in cancer immunotherapy［J］. Immunity, 2020,52（1）:17⁃35. doi: 10.1016/j.immuni.2019.12.011.
［15］	Spranger S, Bao R, Gajewski TF. Melanoma⁃intrinsic β⁃catenin signalling prevents anti⁃tumour immunity［J］. Nature, 2015,523（7559）:231⁃235. doi: 10.1038/nature14404.
［16］	Guerra L, Bonetti L, Brenner D. Metabolic modulation of immunity: a new concept in cancer immunotherapy［J］. Cell Rep, 2020,32（1）:107848. doi: 10.1016/j.celrep.2020.107848.
［17］	Warming "cold" melanoma with TLR9 agonists［J］. Cancer Discov, 2018,8（6）:670. doi: 10.1158/2159⁃8290.CD⁃ND2018⁃004.
［18］	O′Sullivan D, Sanin DE, Pearce EJ, et al. Metabolic interventions in the immune response to cancer［J］. Nat Rev Immunol, 2019,19（5）:324⁃335. doi: 10.1038/s41577⁃019⁃0140⁃9.
［19］	Russell L, Peng KW, Russell SJ, et al. Oncolytic viruses: priming time for cancer immunotherapy［J］. BioDrugs, 2019,33（5）:485⁃501. doi: 10.1007/s40259⁃019⁃00367⁃0.
［20］	Duan Q, Zhang H, Zheng J, et al. Turning cold into hot: firing up the tumor microenvironment［J］. Trends Cancer, 2020,6（7）:605⁃618. doi: 10.1016/j.trecan.2020.02.022.
［21］	Axelrod ML, Johnson DB, Balko JM. Emerging biomarkers for cancer immunotherapy in melanoma［J］. Semin Cancer Biol, 2018,52（Pt 2）:207⁃215. doi: 10.1016/j.semcancer.2017.09.004.
［22］	Havel JJ, Chowell D, Chan TA. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy［J］. Nat Rev Cancer, 2019,19（3）:133⁃150. doi: 10.1038/s41568⁃019⁃0116⁃x.
［23］	Martens A, Wistuba⁃Hamprecht K, Geukes Foppen M, et al. Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab［J］. Clin Cancer Res, 2016,22（12）:2908⁃2918. doi: 10.1158/1078⁃0432.CCR⁃15⁃2412.
［24］	Cristescu R, Mogg R, Ayers M, et al. Pan⁃tumor genomic biomarkers for PD⁃1 checkpoint blockade⁃based immunotherapy［J］. Science, 2018,362（6411）:eaar3593. doi: 10.1126/science.aar3593.
［25］	O′Donnell JS, Long GV, Scolyer RA, et al. Resistance to PD1/PDL1 checkpoint inhibition［J］. Cancer Treat Rev, 2017,52:71⁃81. doi: 10.1016/j.ctrv.2016.11.007.
［26］	Gide TN, Wilmott JS, Scolyer RA, et al. Primary and acquired resistance to immune checkpoint inhibitors in metastatic melanoma［J］. Clin Cancer Res, 2018,24（6）:1260⁃1270. doi: 10.1158/1078⁃0432.CCR⁃17⁃2267.
［27］	Egen JG, Ouyang W, Wu LC. Human anti⁃tumor immunity: insights from immunotherapy clinical trials［J］. Immunity, 2020,52（1）:36⁃54. doi: 10.1016/j.immuni.2019.12.010.
［28］	Fankhauser M, Broggi M, Potin L, et al. Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma［J］. Sci Transl Med, 2017,9（407）:eaal4712. doi: 10.1126/scitranslmed.aal4712.
［29］	Kalbasi A, Ribas A. Tumour⁃intrinsic resistance to immune checkpoint blockade［J］. Nat Rev Immunol, 2020,20（1）:25⁃39. doi: 10.1038/s41577⁃019⁃0218⁃4.
［30］	Zaretsky JM, Garcia⁃Diaz A, Shin DS, et al. Mutations associated with acquired resistance to PD⁃1 blockade in melanoma［J］. N Engl J Med, 2016,375（9）:819⁃829. doi: 10. 1056/NEJMoa1604958.
［31］	Trujillo JA, Luke JJ, Zha Y, et al. Secondary resistance to immunotherapy associated with β⁃catenin pathway activation or PTEN loss in metastatic melanoma［J］. J Immunother Cancer, 2019,7（1）:295. doi: 10.1186/s40425⁃019⁃0780⁃0.
［32］	Hodi FS, Lee S, McDermott DF, et al. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial［J］. JAMA, 2014,312（17）:1744⁃1753. doi: 10.1001/jama.2014.13943.
［33］	Ribas A, Dummer R, Puzanov I, et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti⁃PD⁃1 immunotherapy［J］. Cell, 2017,170（6）:1109⁃1119.e10. doi: 10.1016/j.cell.2017.08.027.
［34］	Li M, Yang Y, Wei J, et al. Enhanced chemo⁃immunotherapy against melanoma by inhibition of cholesterol esterification in CD8+ T cells［J］. Nanomedicine, 2018,14（8）:2541⁃2550. doi: 10.1016/j.nano.2018.08.008.
［35］	Wanderley CW, Colón DF, Luiz J, et al. Paclitaxel reduces tumor growth by reprogramming tumor⁃associated macrophages to an M1 profile in a TLR4⁃dependent manner［J］. Cancer Res, 2018,78（20）:5891⁃5900. doi: 10.1158/0008⁃5472.CAN⁃17⁃3480.
［36］	Williams NL, Wuthrick EJ, Kim H, et al. Phase 1 study of ipilimumab combined with whole brain radiation therapy or radiosurgery for melanoma patients with brain metastases［J］. Int J Radiat Oncol Biol Phys, 2017,99（1）:22⁃30. doi: 10.1016/j.ijrobp.2017.05.028.
［37］	Nass SJ, Rothenberg ML, Pentz R, et al. Accelerating anticancer drug development ⁃ opportunities and trade⁃offs［J］. Nat Rev Clin Oncol, 2018,15（12）:777⁃786. doi: 10.1038/s41571⁃018⁃0102⁃3.
［38］	Simon R. Critical review of umbrella, basket, and platform designs for oncology clinical trials［J］. Clin Pharmacol Ther, 2017,102（6）:934⁃941. doi: 10.1002/cpt.814.
［39］	Wang DY, Johnson DB, Davis EJ. Toxicities associated with PD⁃1/PD⁃L1 blockade［J］. Cancer J, 2018,24（1）:36⁃40. doi: 10. 1097/PPO.0000000000000296.
［40］	Pollack MH, Betof A, Dearden H, et al. Safety of resuming anti⁃PD⁃1 in patients with immune⁃related adverse events （irAEs） during combined anti⁃CTLA⁃4 and anti⁃PD1 in metastatic melanoma［J］. Ann Oncol, 2018,29（1）:250⁃255. doi: 10.1093/annonc/mdx642.
［41］	Irvine DJ, Dane EL. Enhancing cancer immunotherapy with nanomedicine［J］. Nat Rev Immunol, 2020,20（5）:321⁃334. doi: 10.1038/s41577⁃019⁃0269⁃6.
［42］	Phuengkham H, Ren L, Shin IW, et al. Nanoengineered immune niches for reprogramming the immunosuppressive tumor microenvironment and enhancing cancer immunotherapy［J］. Adv Mater, 2019,31（34）:e1803322. doi: 10.1002/adma.201803 322.
［43］	Shi Y, Lammers T. Combining nanomedicine and immunotherapy［J］. Acc Chem Res, 2019, 52（6）:1543⁃1554. doi: 10.1021/acs.accounts.9b00148.
［44］	Xie J, Yang C, Liu Q, et al. Encapsulation of hydrophilic and hydrophobic peptides into hollow mesoporous silica nanoparticles for enhancement of antitumor immune response［J/OL］. Small，2017,13（40）:1701741. https://onlinelibrary.wiley.com/doi/full/10.1002/smll.201701741. doi: 10.1002/smll.201701741.
［45］	Dong L, Li Y, Li Z, et al. Au nanocage⁃strengthened dissolving microneedles for chemo⁃photothermal combined therapy of superficial skin tumors［J］. ACS Appl Mater Interfaces, 2018,10（11）:9247⁃9256. doi: 10.1021/acsami.7b18293.

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黑素瘤免疫治疗的难点及对策

Melanoma immunotherapy: difficulties and strategies

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