肿瘤相关中性粒细胞在免疫检查点抑制剂耐药中的研究进展

doi:10.11904/j.issn.1002-3070.2024.05.011

摘要/Abstract

摘要： 癌症是严重危害人类健康的重大疾病。近年来,免疫检查点抑制剂(Immune checkpoint inhibitors,ICIs)已经改变了多种实体肿瘤的治疗模式。尽管初始治疗效果显著,然而这种疗法的耐药问题已逐渐显现。深入了解ICIs耐药的机制显得尤为重要。肿瘤微环境(Tumor microenvironment,TME)中的中性粒细胞在程序性细胞死亡蛋白-1(Programmed cell death protein-1,PD-1)及其配体抑制剂耐药中起着关键作用。因此,重塑肿瘤相关中性粒细胞(Tumor-associated neutrophils,TANs)不仅可以增强抗肿瘤免疫反应,而且可以在改善患者预后方面做出贡献。本文旨在探讨TANs在ICIs耐药中的潜在作用,并总结当前为克服ICIs耐药所开展的各项努力。

关键词: 肿瘤相关中性粒细胞, 免疫检查点抑制剂, 耐药

Abstract: Cancer is a major disease that seriously endangers human health.In recent years,immune checkpoint inhibitors(ICIs)have changed the paradigm of treatment for various solid tumors.Although the initial treatment effect is significant,the issue of drug resistance in this therapy has gradually become apparent.It is particularly important to have a deep understanding of the mechanisms of ICIs resistance.Neutrophils in the tumor microenvironment(TME)play a critical role in the resistance of programmed cell death protein-1(PD-1)and its ligand inhibitors.Thus,remodeling tumor-associated neutrophils(TANs)can not only enhance the anti-tumor immune response,but also contribute to improving patient prognosis.This article aims to explore the potential role of TANs in ICIs resistance and summarize current efforts to overcome ICIs resistance.

Key words: Tumor-associated neutrophils, Immune checkpoint inhibitors, Drug resistance

中图分类号:

R730.5

韩晶, 关泉林. 肿瘤相关中性粒细胞在免疫检查点抑制剂耐药中的研究进展[J]. 实用肿瘤学杂志, 2024, 38(5): 349-354.

HAN Jing, GUAN Quanlin. Research progress of tumor-associated neutrophils in immune checkpoint inhibitors resistance[J]. Journal of Practical Oncology, 2024, 38(5): 349-354.

参考文献

1 Siegel RL,Miller KD,Fuchs HE,et al.Cancer statistics,2022[J].CA Cancer J Clin,2022,72(1):7-33.
2 Debela DT,Muzazu SG,Heraro KD,et al.New approaches and procedures for cancer treatment:current perspectives[J].SAGE Open Med,2021,9:20503121211034366.
3 Ribas A,Wolchok JD.Cancer immunotherapy using checkpoint blockade[J].Science,2018,359(6382):1350-1355.
4 Huang Z,Su W,Lu T,et al.First-line immune-checkpoint inhibitors in non-small cell lung cancer:current landscape and future progress[J].Front Pharmacol,2020,11:578091.
5 Cohen EEW,Soulières D,Le Tourneau C,et al.Pembrolizumab versus methotrexate,docetaxel,or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma(KEYNOTE-040):a randomised,open-label,phase 3 study[J].Lancet,2019,393(10167):156-167.
6 Bagchi S,Yuan R,Engleman EG.Immune checkpoint inhibitors for the treatment of cancer:clinical impact and mechanisms of response and resistance[J].Annu Rev Pathol,2021,16(1):223-249.
7 Wang Z,Wang Y,Gao P,et al.Immune checkpoint inhibitor resistance in hepatocellular carcinoma[J].Cancer Lett,2023,555:216038.
8 Genova C,Dellepiane C,Carrega P,et al.Therapeutic implications of tumor microenvironment in lung cancer:focus on immune checkpoint blockade[J].Front Immunol,2022,12:799455.
9 Faget J,Peters S,Quantin X,et al.Neutrophils in the era of immune checkpoint blockade[J].J Immunother Cancer,2021,9(7):e002242.
10 Zhang X,Shi H,Yuan X,et al.Tumor-derived exosomes induce N2 polarization of neutrophils to promote gastric cancer cell migration[J].Mol Cancer,2018,17(1):146.
11 Hattar K,Franz K,Ludwig M,et al.Interactions between neutrophils and non-small cell lung cancer cells:enhancement of tumor proliferation and inflammatory mediator synthesis[J].Cancer Immunol Immunother,2014,63(12):1297-1306.
12 Peng W,Sheng Y,Xiao H,et al.Lung adenocarcinoma cells promote self-migration and self-invasion by activating neutrophils to upregulate notch3 expression of cancer cells[J].Front Mol Biosci,2022,8:762729.
13 Sagiv JY,Michaeli J,Assi S,et al.Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer[J].Cell Rep,2015,10(4):562-573.
14 Shaul ME,Fridlender ZG.Tumour-associated neutrophils in patients with cancer[J].Nat Rev Clin Oncol,2019,16(10):601-620.
15 Wu L,Saxena S,Awaji M,et al.Tumor-associated neutrophils in cancer:going pro[J].Cancers,2019,11(4):564.
16 Bui TM,Yalom LK,Sumagin R.Tumor-associated neutrophils:orchestrating cancer pathobiology and therapeutic resistance[J].Expert Opin Ther Targets,2021,25(7):573-583.
17 Kwantwi LB.Interplay between tumor-derived factors and tumor-associated neutrophils:opportunities for therapeutic interventions in cancer[J].Clin Transl Oncol,2023,25(7):1963-1976.
18 Kamran N,Kadiyala P,Saxena M,et al.Immunosuppressive myeloid cells′ blockade in the glioma microenvironment enhances the efficacy of immune-stimulatory gene therapy[J].Mol Ther,2017,25(1):232-248.
19 Tang D,Zhang D,Heng Y,et al.Tumor-infiltrating PD-L1+ neutrophils induced by GM-CSF suppress T cell function in laryngeal squamous cell carcinoma and predict unfavorable prognosis[J].J Inflamm Res,2022,15:1079-1097.
20 Sun R,Xiong Y,Liu H,et al.Tumor-associated neutrophils suppress antitumor immunity of NK cells through the PD-L1/PD-1 axis[J].Transl Oncol,2020,13(10):100825.
21 Shang A,Wang W,Gu C,et al.Long non-coding RNA HOTTIP enhances IL-6 expression to potentiate immune escape of ovarian cancer cells by upregulating the expression of PD-L1 in neutrophils[J].J Exp Clin Cancer Res,2019,38(1):411.
22 Wang TT,Zhao YL,Peng LS,et al.Tumour-activated neutrophils in gastric cancer foster immune suppression and disease progression through GM-CSF-PD-L1 pathway[J].Gut,2017,66(11):1900-1911.
23 Shi Y,Zhang J,Mao Z,et al.Extracellular vesicles from gastric cancer cells induce PD-L1 expression on neutrophils to suppress T-cell immunity[J].Front Oncol,2020,10:629.
24 Cheng Y,Li H,Deng Y,et al.Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma[J].Cell Death Dis,2018,9(4):422.
25 He G,Zhang H,Zhou J,et al.Peritumoural neutrophils negatively regulate adaptive immunity via the PD-L1/PD-1 signalling pathway in hepatocellular carcinoma[J].J Exp Clin Cancer Res,2015,34(1):141.
26 Arasanz H,Bocanegra AI,Morilla I,et al.Circulating low density neutrophils are associated with resistance to first line Anti-PD1/PDL1 immunotherapy in non-small cell lung cancer[J].Cancers,2022,14(16):3846.
27 Wong SL,Wagner DD.Peptidylarginine deiminase 4:a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging[J].FASEB J,2018,32(12):6258-6370.
28 Brinkmann V,Reichard U,Goosmann C,et al.Neutrophil extracellular traps kill bacteria[J].Science,2004,303(5663):1532-1535.
29 Teijeira á,Garasa S,Gato M,et al.CXCR1 and CXCR2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity[J].Immunity,2020,52(5):856-871.
30 Wang R,Zhu Y,Liu Z,et al.Neutrophil extracellular traps promote tPA-induced brain hemorrhage via cGAS in mice with stroke[J].Blood,2021,138(1):91-103.
31 Chen D,Li Q,Liang H,et al.Exenatide enhanced the antitumor efficacy on PD-1 blockade by the attenuation of neutrophil extracellular traps[J].Biochem Biophys Res Commun,2022,619:97-103.
32 Zhang H,Wang Y,Onuma A,et al.Neutrophils extracellular traps inhibition improves PD-1 blockade immunotherapy in colorectal cancer[J].Cancers,2021,13(21):5333.
33 Zhang Y,Chandra V,Riquelme Sanchez E,et al.Interleukin-17-induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer[J].J Exp Med,2020,217(12):e20190354.
34 Akbay EA,Koyama S,Liu Y,et al.Interleukin-17A promotes lung tumor progression through neutrophil attraction to tumor sites and mediating resistance to PD-1 blockade[J].J Thorac Oncol,2017,12(8):1268-1279.
35 Kim GT,Kim EY,Shin SH,et al.Improving anticancer effect of aPD-L1 through lowering neutrophil infiltration by PLAG in tumor implanted with MB49 mouse urothelial carcinoma[J].BMC Cancer,2022,22(1):727.
36 Simoncello F,Piperno GM,Caronni N,et al.CXCL5-mediated accumulation of mature neutrophils in lung cancer tissues impairs the differentiation program of anticancer CD8 T cells and limits the efficacy of checkpoint inhibitors[J].Oncoimmunology,2022,11(1):2059876.
37 Sun L,Clavijo PE,Robbins Y,et al.Inhibiting myeloid-derived suppressor cell trafficking enhances T cell immunotherapy[J].JCI Insight,2019,4(7):e126853.
38 D′Alterio C,Barbieri A,Portella L,et al.Inhibition of stromal CXCR4 impairs development of lung metastases[J].Cancer Immunol Immunother,2012,61(10):1713-1720.
39 Bockorny B,Semenisty V,Macarulla T,et al.BL-8040,a CXCR4 antagonist,in combination with pembrolizumab and chemotherapy for pancreatic cancer:the COMBAT trial[J].Nat Med,2020,26(6):878-885.
40 Kaunisto A,Henry WS,Montaser-Kouhsari L,et al.NFAT1 promotes intratumoral neutrophil infiltration by regulating IL8 expression in breast cancer[J].Mol Oncol,2015,9(6):1140-1154.
41 Cai Z,Zhang M,Boafo Kwantwi L,et al.Breast cancer cells promote self-migration by secreting interleukin 8 to induce NET formation[J].Gene,2020,754:144902.
42 Denk S,Taylor RP,Wiegner R,et al.Complement C5a‐induced changes in neutrophil morphology during inflammation[J].Scand J Immunol,2017,86(3):143-155.
43 Allen E,Jabouille A,Rivera LB,et al.Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation[J].Sci Transl Med,2017,9(385):9679.
44 Ott PA,Hodi FS,Buchbinder EI.Inhibition of immune checkpoints and vascular endothelial growth factor as combination therapy for metastatic melanoma:an overview of rationale,preclinical evidence,and initial clinical data[J].Front Oncol,2015,5:202.
45 Taylor MH,Lee CH,Makker V,et al.Phase IB/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma,endometrial cancer,and other selected advanced solid tumors[J].J Clin Oncol,2020,38(11):1154-1163.
46 Amin A,Plimack ER,Ernstoff MS,et al.Correction to:safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma:the checkmate 016 study[J].J Immunother Cancer,2019,7(1):73.
47 Kauder SE,Kuo TC,Harrabi O,et al.ALX148 blocks CD47 and enhances innate and adaptive antitumor immunity with a favorable safety profile[J].Plos One,2018,13(8):e0201832.
48 Lakhani NJ,Chow LQM,Gainor JF,et al.Evorpacept alone and in combination with pembrolizumab or trastuzumab in patients with advanced solid tumours(ASPEN-01):a first-in-human,open-label,multicentre,phase 1 dose-escalation and dose-expansion study[J].Lancet Oncol,2021,22(12):1740-1751.
49 Ansell SM,Maris MB,Lesokhin AM,et al.Phase I study of the CD47 blocker TTI-621 in patients with relapsed or refractory hematologic malignancies[J].Clin Cancer Res,2021,27(8):2190-2199.
50 Bockorny B,Macarulla T,Semenisty V,et al.Motixafortide and pembrolizumab combined to nanoliposomal irinotecan,fluorouracil,and folinic acid in metastatic pancreatic cancer:the COMBAT/KEYNOTE-202 trial[J].Clin Cancer Res,2021,27(18):5020-5027.
51 Andtbacka RHI,Wang Y,Pierce RH,et al.Mavorixafor,an orally bioavailable CXCR4 antagonist,increases immune cell infiltration and inflammatory status of tumor microenvironment in patients with melanoma[J].Cancer Res Commun,2022,2(8):904-913.
52 Choueiri TK,Atkins MB,Rose TL,et al.A phase 1b trial of the CXCR4 inhibitor mavorixafor and nivolumab in advanced renal cell carcinoma patients with no prior response to nivolumab monotherapy[J].Invest New Drugs,2021,39(4):1019-1027.
53 Armstrong AJ,Geva R,Chung HC,et al.CXCR2 antagonist navarixin in combination with pembrolizumab in select advanced solid tumors:a phase 2 randomized trial[J].Invest New Drugs,2024,42(1):145-159.
54 Garrido P,Pujol JL,Kim ES,et al.Canakinumab with and without pembrolizumab in patients with resectable non-small-cell lung cancer:CANOPY-N study design[J].Future Oncol,2021,17(12):1459-1472.
55 Tan DSW,Felip E,de Castro G,et al.Canakinumab versus placebo in combination with first-line pembrolizumab plus chemotherapy for advanced non-small-cell lung cancer:results from the CANOPY-1 trial.[J].J Clin Oncol,2024,42(2):192-204.
56 Chen IM,Donia M,Chamberlain CA,et al.Phase 2 study of ipilimumab,nivolumab,and tocilizumab combined with stereotactic body radiotherapy in patients with refractory pancreatic cancer(TRIPLE-R)[J].Eur J Cancer,2023,180:125-133.
57 Munster P,Iannotti N,Cho DC,et al.Combination of itacitinib or parsaclisib with pembrolizumab in patients with advanced solid tumors:a phase I study[J].Cancer Res Commun,2023,3(12):2572-2584.

[1]	庞琬莹, 安静, 刘兆良. TRIM24在乳腺癌内分泌治疗耐药中的作用及机制研究[J]. 实用肿瘤学杂志, 2024, 38(6): 402-409.
[2]	何佳颖, 朱津丽, 贾凯旋, 杨佩颖. IFN-γ在肿瘤免疫检查点抑制剂治疗中的研究进展[J]. 实用肿瘤学杂志, 2024, 38(5): 330-335.
[3]	孙莉君, 董大伟. 基于铂类耐药相关基因的卵巢癌分型和预后研究[J]. 实用肿瘤学杂志, 2024, 38(3): 184-191.
[4]	赵璐, 张正凤, 王大臻, 杨柳, 刘泽, 娄长杰. 免疫治疗在实体瘤中的应用现状[J]. 实用肿瘤学杂志, 2024, 38(1): 55-61.
[5]	尚宏悦, 姚曼曼, 路月亭, 王迪娴, 赵乾, 刘铁军. lncRNA CASC2与肿瘤化疗耐药实验研究进展[J]. 实用肿瘤学杂志, 2024, 38(1): 67-70.
[6]	曹新玉, 周旭, 汪泉, 姜伟. 癌症药物耐药潜在机制及预测方法[J]. 实用肿瘤学杂志, 2023, 37(6): 491-495.
[7]	初思彤, 许庆勇. 三阴性乳腺癌免疫治疗耐药机制的研究进展[J]. 实用肿瘤学杂志, 2023, 37(5): 449-453.
[8]	王新萍, 张自云, 王学东. 非编码RNA在乳腺癌化疗耐药中作用的研究进展[J]. 实用肿瘤学杂志, 2023, 37(5): 454-458.
[9]	张岩, 田素礼, 周勇旭, 刘昶. miR-7调控结直肠癌细胞对5-氟尿嘧啶敏感性的机制研究[J]. 实用肿瘤学杂志, 2023, 37(4): 320-328.
[10]	李福程, 贾斯媛, 巴玉玲, 罗丹利, 肖敏. 免疫检查点抑制剂在早期乳腺癌新辅助治疗中的研究进展[J]. 实用肿瘤学杂志, 2023, 37(4): 367-371.
[11]	龙朝恋, 李琨, 刘子臣, 张娜娜, 车南颖. 非小细胞肺癌程序性死亡配体-1表达与临床病理特征和常见驱动基因变异的相关性研究[J]. 实用肿瘤学杂志, 2023, 37(2): 117-122.
[12]	冯诚天, 黄芙蓉, 姜永冬. 脂质代谢与乳腺癌曲妥珠单抗耐药性机制的相关性研究[J]. 实用肿瘤学杂志, 2023, 37(2): 155-159.
[13]	杨磊, 张正凤, 王大榛, 娄长杰. 基于真实世界的晚期食管鳞癌一线标准化疗联合免疫检查点抑制剂对比标准化疗的回顾性对照研究[J]. 实用肿瘤学杂志, 2022, 36(6): 538-543.
[14]	王星涵, 吕雅蕾. 曲妥珠单抗耐药机制及HER2阳性乳腺癌耐药后的治疗策略[J]. 实用肿瘤学杂志, 2022, 36(5): 445-451.
[15]	李雄, 姜文凯, 郎泽昆, 芮少珍. 肿瘤相关中性粒细胞与胰腺癌关系的研究进展[J]. 实用肿瘤学杂志, 2022, 36(5): 458-462.