上海交通大学学报（医学版）

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2024 , Vol. 44 >Issue 7: 830 - 838

DOI: https://doi.org/10.3969/j.issn.1674-8115.2024.07.004

转化医学研究前沿进展专题

肿瘤微环境免疫细胞调节肿瘤细胞耐药性的研究进展

  • 张烨晟 ,
  • 杨易静 ,
  • 黄依雯 ,
  • 施珑玙 ,
  • 王曼媛 ,
  • 陈思思
展开
  • 1.上海交通大学医学院附属上海儿童医学中心儿科转化医学研究所，上海 200127
    2.上海交通大学医学院附属胸科医院胸部肿瘤研究所，上海 200030
    3.上海交通大学医学院附属仁济医院干细胞研究中心，上海 200127
    4.上海交通大学医学院医学技术学院，上海 200025
    5.上海交通大学医学院附属第一人民医院疑难疾病精准研究中心，上海 201600
张烨晟（2001—），男，博士生；电子信箱：yesheng_zhang@163.com。
陈思思，电子信箱：sisichen@shsmu.edu.cn。

收稿日期: 2024-01-30

  录用日期: 2024-04-28

  网络出版日期: 2024-07-28

基金资助

上海市浦江人才计划(23PJ1410400)

收起

Research progress in immune cells regulating drug resistance of tumor cells in tumor microenvironment

  • Yesheng ZHANG ,
  • Yijing YANG ,
  • Yiwen HUANG ,
  • Longyu SHI ,
  • Manyuan WANG ,
  • Sisi CHEN
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  • 1.Pediatric Translational Medicine Institute, Shanghai Children′s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
    2.Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
    3.Clinical Stem Cell Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
    4.College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
    5.Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China
CHEN Sisi, E-mail: sisichen@shsmu.edu.cn.

Received date: 2024-01-30

  Accepted date: 2024-04-28

  Online published: 2024-07-28

Supported by

Shanghai Pujiang Program(23PJ1410400)

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摘要

肿瘤微环境（tumor microenvironment，TME）是肿瘤细胞生存的复杂细胞环境，内含多种类型的细胞和围绕肿瘤细胞的细胞外成分。免疫细胞是TME的关键组成部分，包括肿瘤相关巨噬细胞（tumor-associated macrophages，TAMs）、髓系抑制性细胞（myeloid-derived suppressor cells，MDSCs）、淋巴细胞、调节性T细胞（regulatory T cells，Tregs）、自然杀伤细胞（natural killer cells，NK cells）及树突状细胞（dendritic cells，DCs）等。值得关注的是，目前肿瘤耐药是化学治疗（化疗）、放射治疗（放疗）、靶向治疗及免疫治疗等肿瘤治疗方法疗效受限并导致治疗失败的主要原因。研究发现，肿瘤细胞耐药性的产生是肿瘤细胞与TME相互作用的结果。因此，如何克服TME所致肿瘤耐药被认为是肿瘤治疗的一大难点。近年来，随着对TME中免疫细胞研究的深入，免疫细胞调节肿瘤细胞耐药性的具体机制研究取得重大进展，而靶向相应免疫细胞、信号通路或细胞因子的治疗策略被证实能够有效减少肿瘤耐药并改善肿瘤治疗效果。该文就TME中TAMs、MDSCs、Tregs和NK细胞等在肿瘤耐药中发挥的作用及克服肿瘤耐药的靶向策略的研究进展进行综述，并讨论肿瘤相关中性粒细胞（tumor-associated neutrophils，TANs）和免疫抑制性调节性B细胞（B regulatory cells，Bregs）与肿瘤耐药之间的关系，以期为克服肿瘤耐药和提高抗肿瘤治疗效果提供方向和参考。

关键词： 肿瘤微环境; 耐药; 肿瘤相关巨噬细胞; 髓系抑制性细胞; 调节性T细胞; 自然杀伤细胞

本文引用格式

张烨晟 , 杨易静 , 黄依雯 , 施珑玙 , 王曼媛 , 陈思思 . 肿瘤微环境免疫细胞调节肿瘤细胞耐药性的研究进展[J]. 上海交通大学学报（医学版）, 2024 , 44(7) : 830 -838 . DOI: 10.3969/j.issn.1674-8115.2024.07.004

Abstract

Tumor microenvironment (TME) is a complex cellular environment where tumor cells reside, along with various types of cells and extracellular components surrounding the tumor cells. Immune cells are key components of TME, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), lymphocytes, regulatory T cells (Tregs), natural killer cells (NK cells), dendritic cells (DCs), and many others. It is worth noting that drug resistance is currently a major factor limiting the efficacy of cancer treatment methods such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy, and a leading cause of treatment failure. Research has found that the development of drug resistance in tumor cells is the result of interactions between tumor cells and TME. Consequently, overcoming drug resistance in tumors caused by TME is considered a significant challenge in cancer treatment. In recent years, with in-depth research into immune cells within TME, significant progress has been made in understanding the specific mechanisms by which immune cells regulate drug resistance in tumor cells. Furthermore, therapeutic strategies that target these immune cells, signaling pathways, or cytokines have been shown to effectively combat tumor drug resistance and enhance the therapeutic outcomes of cancer treatment. This article reviews the research advancements regarding the roles of TAMs, MDSCs, Tregs, and NK cells in tumor drug resistance within TME and discusses the development of targeting strategies to overcome this resistance. Additionally, we explore the relationship of tumor-associated neutrophils (TANs) and B regulatory cells (Bregs) with tumor drug resistance. It is hoped that this review will offer insights and serve as reference for reducing tumor drug resistance and improving the efficacy of anti-tumor therapies.

Key words： tumor microenvironment (TME); drug resistance; tumor-associated macrophage (TAM); myeloid-derived suppressor cell (MDSC); regulatory T cell (Treg); natural killer cell (NK cell)

参考文献

1 HANAHAN D, COUSSENS L M. Accessories to the crime: functions of cells recruited to the tumor microenvironment[J]. Cancer Cell, 2012, 21(3): 309-322.
2 ANDERSON N M, SIMON M C. The tumor microenvironment[J]. Curr Biol, 2020, 30(16): R921-R925.
3 FU T, DAI L J, WU S Y, et al. Spatial architecture of the immune microenvironment orchestrates tumor immunity and therapeutic response[J]. J Hematol Oncol, 2021, 14(1): 98.
4 DUAN Q Q, ZHANG H L, ZHENG J N, et al. Turning cold into hot: firing up the tumor microenvironment[J]. Trends Cancer, 2020, 6(7): 605-618.
5 SUN Y. Tumor microenvironment and cancer therapy resistance[J]. Cancer Lett, 2016, 380(1): 205-215.
6 MANTOVANI A, ALLAVENA P, SICA A, et al. Cancer-related inflammation[J]. Nature, 2008, 454(7203): 436-444.
7 SHARMA P, HU-LIESKOVAN S, WARGO J A, et al. Primary, adaptive, and acquired resistance to cancer immunotherapy[J]. Cell, 2017, 168(4): 707-723.
8 POTT S, LIEB J D. Single-cell ATAC-seq: strength in numbers[J]. Genome Biol, 2015, 16(1): 172.
9 SOLINAS G, GERMANO G, MANTOVANI A, et al. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation[J]. J Leukoc Biol, 2009, 86(5): 1065-1073.
10 CHIM L K, WILLIAMS I L, BASHOR C J, et al. Tumor-associated macrophages induce inflammation and drug resistance in a mechanically tunable engineered model of osteosarcoma[J]. Biomaterials, 2023, 296: 122076.
11 BOUTILIER A J, ELSAWA S F. Macrophage polarization states in the tumor microenvironment[J]. Int J Mol Sci, 2021, 22(13): 6995.
12 GINHOUX F, GUILLIAMS M. Tissue-resident macrophage ontogeny and homeostasis[J]. Immunity, 2016, 44(3): 439-449.
13 MILLS C D, KINCAID K, ALT J M, et al. M-1/M-2 macrophages and the Th1/Th2 paradigm[J]. J Immunol, 2000, 164(12): 6166-6173.
14 WANG L X, ZHANG S X, WU H J, et al. M2b macrophage polarization and its roles in diseases[J]. J Leukoc Biol, 2019, 106(2): 345-358.
15 JEANNIN P, PAOLINI L, ADAM C, et al. The roles of CSFs on the functional polarization of tumor-associated macrophages[J]. FEBS J, 2018, 285(4): 680-699.
16 CHRISTOFIDES A, STRAUSS L, YEO A, et al. The complex role of tumor-infiltrating macrophages[J]. Nat Immunol, 2022, 23(8): 1148-1156.
17 MOSSER D M, EDWARDS J P. Exploring the full spectrum of macrophage activation[J]. Nat Rev Immunol, 2008, 8(12): 958-969.
18 KHALAF K, HANA D, CHOU J T T, et al. Aspects of the tumor microenvironment involved in immune resistance and drug resistance[J]. Front Immunol, 2021, 12: 656364.
19 MA J, SHAYITI F, MA J, et al. Tumor-associated macrophage-derived CCL5 promotes chemotherapy resistance and metastasis in prostatic cancer[J]. Cell Biol Int, 2021, 45(10): 2054-2062.
20 WANG H C, HAUNG L Y, WANG C J, et al. Tumor-associated macrophages promote resistance of hepatocellular carcinoma cells against sorafenib by activating CXCR2 signaling[J]. J Biomed Sci, 2022, 29(1): 99.
21 LI D B, JI H F, NIU X J, et al. Tumor-associated macrophages secrete CC-chemokine ligand 2 and induce tamoxifen resistance by activating PI3K/Akt/mTOR in breast cancer[J]. Cancer Sci, 2020, 111(1): 47-58.
22 LI H, LUO F, JIANG X Y, et al. CircITGB6 promotes ovarian cancer cisplatin resistance by resetting tumor-associated macrophage polarization toward the M2 phenotype[J]. J Immunother Cancer, 2022, 10(3): e004029.
23 ZHANG H, LIU L, LIU J B, et al. Roles of tumor-associated macrophages in anti-PD-1/PD-L1 immunotherapy for solid cancers[J]. Mol Cancer, 2023, 22(1): 58.
24 TSUKAMOTO M, IMAI K, ISHIMOTO T, et al. PD-L1 expression enhancement by infiltrating macrophage-derived tumor necrosis factor-α leads to poor pancreatic cancer prognosis[J]. Cancer Sci, 2019, 110(1): 310-320.
25 CHEN Y J, LI G N, LI X J, et al. Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy[J]. Sci Adv, 2023, 9(17): eadg0654.
26 YUAN S Y, CHEN W J, YANG J, et al. Tumor-associated macrophage-derived exosomes promote EGFR-TKI resistance in non-small cell lung cancer by regulating the AKT, ERK1/2 and STAT3 signaling pathways[J]. Oncol Lett, 2022, 24(4): 356.
27 LIU C, ZHAO Z L, GUO S K, et al. Exosomal miR-27a-3p derived from tumor-associated macrophage suppresses propranolol sensitivity in infantile hemangioma[J]. Cell Immunol, 2021, 370: 104442.
28 CHEN C, ZHANG L, RUAN Z Y. GATA3 encapsulated by tumor-associated macrophage-derived extracellular vesicles promotes immune escape and chemotherapy resistance of ovarian cancer cells by upregulating the CD24/siglec-10 axis[J]. Mol Pharm, 2023, 20(2): 971-986.
29 XIA Y Q, RAO L, YAO H M, et al. Engineering macrophages for cancer immunotherapy and drug delivery[J]. Adv Mater, 2020, 32(40): e2002054.
30 RODRIGUEZ-GARCIA A, LYNN R C, POUSSIN M, et al. CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy[J]. Nat Commun, 2021, 12(1): 877.
31 GUNASSEKARAN G R, POONGKAVITHAI VADEVOO S M, BAEK M C, et al. M1 macrophage exosomes engineered to foster M1 polarization and target the IL-4 receptor inhibit tumor growth by reprogramming tumor-associated macrophages into M1-like macrophages[J]. Biomaterials, 2021, 278: 121137.
32 LI C X, XU X F, WEI S H, et al. Tumor-associated macrophages: potential therapeutic strategies and future prospects in cancer[J]. J Immunother Cancer, 2021, 9(1): e001341.
33 CASSETTA L, POLLARD J W. A timeline of tumour-associated macrophage biology[J]. Nat Rev Cancer, 2023, 23(4): 238-257.
34 SIKIC B I, LAKHANI N, PATNAIK A, et al. First-in-human, first-in-class phase Ⅰ trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers[J]. J Clin Oncol, 2019, 37(12): 946-953.
35 ADVANI R, FLINN I, POPPLEWELL L, et al. CD47 blockade by Hu5F9-G4 and rituximab in non-Hodgkin′s lymphoma[J]. N Engl J Med, 2018, 379(18): 1711-1721.
36 VEGLIA F, SANSEVIERO E, GABRILOVICH D I. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity[J]. Nat Rev Immunol, 2021, 21(8): 485-498.
37 RODRíGUEZ P C, OCHOA A C. Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives[J]. Immunol Rev, 2008, 222: 180-191.
38 CIMEN BOZKUS C, ELZEY B D, CRIST S A, et al. Expression of cationic amino acid transporter 2 is required for myeloid-derived suppressor cell-mediated control of T cell immunity[J]. J Immunol, 2015, 195(11): 5237-5250.
39 BAUMANN T, DUNKEL A, SCHMID C, et al. Regulatory myeloid cells paralyze T cells through cell-cell transfer of the metabolite methylglyoxal[J]. Nat Immunol, 2020, 21(5): 555-566.
40 ANTONIOS J P, SOTO H, EVERSON R G, et al. Immunosuppressive tumor-infiltrating myeloid cells mediate adaptive immune resistance via a PD-1/PD-L1 mechanism in glioblastoma[J]. Neuro Oncol, 2017, 19(6): 796-807.
41 PICO DE COA?A Y, POSCHKE I, GENTILCORE G, et al. Ipilimumab treatment results in an early decrease in the frequency of circulating granulocytic myeloid-derived suppressor cells as well as their Arginase1 production[J]. Cancer Immunol Res, 2013, 1(3): 158-162.
42 DOLCETTI L, PERANZONI E, UGEL S, et al. Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF[J]. Eur J Immunol, 2010, 40(1): 22-35.
43 MILLRUD C R, BERGENFELZ C, LEANDERSSON K. On the origin of myeloid-derived suppressor cells[J]. Oncotarget, 2017, 8(2): 3649-3665.
44 NEFEDOVA Y, NAGARAJ S, ROSENBAUER A, et al. Regulation of dendritic cell differentiation and antitumor immune response in cancer by pharmacologic-selective inhibition of the Janus-activated kinase 2/signal transducers and activators of transcription 3 pathway[J]. Cancer Res, 2005, 65(20): 9525-9535.
45 NI X L, HU G H, CAI X. The success and the challenge of all-trans retinoic acid in the treatment of cancer[J]. Crit Rev Food Sci Nutr, 2019, 59(sup1): S71-S80.
46 FUJITA M, KOHANBASH G, FELLOWS-MAYLE W, et al. COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells[J]. Cancer Res, 2011, 71(7): 2664-2674.
47 AL-KHAMI A A, ZHENG L Q, DEL VALLE L, et al. Exogenous lipid uptake induces metabolic and functional reprogramming of tumor-associated myeloid-derived suppressor cells[J]. Oncoimmunology, 2017, 6(10): e1344804.
48 JIAN S L, CHEN W W, SU Y C, et al. Glycolysis regulates the expansion of myeloid-derived suppressor cells in tumor-bearing hosts through prevention of ROS-mediated apoptosis[J]. Cell Death Dis, 2017, 8(5): e2779.
49 ZITVOGEL L, APETOH L, GHIRINGHELLI F, et al. Immunological aspects of cancer chemotherapy[J]. Nat Rev Immunol, 2008, 8(1): 59-73.
50 ERIKSSON E, WENTHE J, IRENAEUS S, et al. Gemcitabine reduces MDSCs, Tregs and TGFβ-1 while restoring the Teff/Treg ratio in patients with pancreatic cancer[J]. J Transl Med, 2016, 14(1): 282.
51 SAKAGUCHI S, SAKAGUCHI N, ASANO M, et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases[J]. J Immunol, 1995, 155(3): 1151-1164.
52 EXPOSITO F, REDRADO M, HOURY M, et al. PTEN loss confers resistance to anti-PD-1 therapy in non-small cell lung cancer by increasing tumor infiltration of regulatory T cells[J]. Cancer Res, 2023, 83(15): 2513-2526.
53 MARSHALL L A, MARUBAYASHI S, JORAPUR A, et al. Tumors establish resistance to immunotherapy by regulating Treg recruitment via CCR4[J]. J Immunother Cancer, 2020, 8(2): e000764.
54 GAO Y N, YOU M J, FU J L, et al. Intratumoral stem-like CCR4+ regulatory T cells orchestrate the immunosuppressive microenvironment in HCC associated with hepatitis B[J]. J Hepatol, 2022, 76(1): 148-159.
55 D'ALISE A M, LEONI G, LUCIA M D, et al. Maximizing cancer therapy via complementary mechanisms of immune activation: PD-1 blockade, neoantigen vaccination, and Tregs depletion[J]. J Immunother Cancer, 2021, 9(11): e003480.
56 FONG W, LI Q, JI F F, et al. Lactobacillus gallinarum-derived metabolites boost anti-PD1 efficacy in colorectal cancer by inhibiting regulatory T cells through modulating IDO1/Kyn/AHR axis[J]. Gut, 2023, 72(12): 2272-2285.
57 IMBERT C, MONTFORT A, FRAISSE M, et al. Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1[J]. Nat Commun, 2020, 11(1): 437.
58 LI Z T, DENG Y Y, SUN H H, et al. Redox modulation with a perfluorocarbon nanoparticle to reverse Treg-mediated immunosuppression and enhance anti-tumor immunity[J]. J Control Release, 2023, 358: 579-590.
59 PIPER M, VAN COURT B, MUELLER A, et al. Targeting Treg-expressed STAT3 enhances NK-mediated surveillance of metastasis and improves therapeutic response in pancreatic adenocarcinoma[J]. Clin Cancer Res, 2022, 28(5): 1013-1026.
60 REVENKO A, CARNEVALLI L S, SINCLAIR C, et al. Direct targeting of FOXP3 in Tregs with AZD8701, a novel antisense oligonucleotide to relieve immunosuppression in cancer[J]. J Immunother Cancer, 2022, 10(4): e003892.
61 AMOOZGAR Z, KLOEPPER J, REN J, et al. Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas[J]. Nat Commun, 2021, 12(1): 2582.
62 TANG F, LI J H, QI L, et al. A pan-cancer single-cell panorama of human natural killer cells[J]. Cell, 2023, 186(19): 4235-4251.e20.
63 LI L, MOHANTY V, DOU J Z, et al. Loss of metabolic fitness drives tumor resistance after CAR-NK cell therapy and can be overcome by cytokine engineering[J]. Sci Adv, 2023, 9(30): eadd6997.
64 MYERS J A, MILLER J S. Exploring the NK cell platform for cancer immunotherapy[J]. Nat Rev Clin Oncol, 2021, 18(2): 85-100.
65 FANTINI M, ARLEN P M, TSANG K Y. Potentiation of natural killer cells to overcome cancer resistance to NK cell-based therapy and to enhance antibody-based immunotherapy[J]. Front Immunol, 2023, 14: 1275904.
66 LUO H Y, ZHOU Y H, ZHANG J, et al. NK cell-derived exosomes enhance the anti-tumor effects against ovarian cancer by delivering cisplatin and reactivating NK cell functions[J]. Front Immunol, 2022, 13: 1087689.
67 NAKAMURA T, SATO T, ENDO R, et al. STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation[J]. J Immunother Cancer, 2021, 9(7): e002852.
68 VALERI A, GARCíA-ORTIZ A, CASTELLANO E, et al. Overcoming tumor resistance mechanisms in CAR-NK cell therapy[J]. Front Immunol, 2022, 13: 953849.
69 ZUO H, YANG M J, JI Q, et al. Targeting neutrophil extracellular traps: a novel antitumor strategy[J]. J Immunol Res, 2023, 2023: 5599660.
70 MOUSSET A, LECORGNE E, BOURGET I, et al. Neutrophil extracellular traps formed during chemotherapy confer treatment resistance via TGF-β activation[J]. Cancer Cell, 2023, 41(4): 757-775.e10.
71 FLORES-BORJA F, BOSMA A, NG D, et al. CD19+CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation[J]. Sci Transl Med, 2013, 5(173): 173ra23.
72 ZHOU X, SU Y X, LAO X M, et al. CD19+IL-10+ regulatory B cells affect survival of tongue squamous cell carcinoma patients and induce resting CD4+ T cells to CD4+Foxp3+ regulatory T cells[J]. Oral Oncol, 2016, 53: 27-35.
73 LI S R, MIRLEKAR B, JOHNSON B M, et al. STING-induced regulatory B cells compromise NK function in cancer immunity[J]. Nature, 2022, 610(7931): 373-380.
74 BARTOSI?SKA J, PURKOT J, KARCZMARCZYK A, et al. Differential function of a novel population of the CD19+CD24hiCD38hi Bregs in psoriasis and multiple myeloma[J]. Cells, 2021, 10(2): 411.
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