Neutrophils in the tumor microenvironment: role in tumor progression and potential targeted therapeutic strategy

Abstract

Neutrophils are known as the body's first line of defense against invading pathogens, which are the most abundant bone-marrow-derived innate immune cells accounting for 50%-70% of all white blood cells in human peripheral blood. With in-depth research in recent years, neutrophils have also been recognized as one of the main immune cells in the tumor microenvironment (TME), playing an important role in tumor development. Neutrophils can promote tumor metastasis through secretion of chemokines and cytokines and formation of neutrophil extracellular traps (NETs). Also, neutrophil targeting treatment has shown a promising anticancer effect. In this article, we summarized the recent research progress related to the significant role of neutrophils in tumor metastasis, as well as the current progression and limitations of targeting neutrophils in tumor therapeutics. This review can provide a comprehensive understanding of the role of neutrophils in the TME and the development of a new anticancer strategy.

Keywords

Neutrophils / metastasis / tumor microenvironment / targeting neutrophil

References

[1] Paget S.The distribution of secondary growths in cancer of the breast.1889.Cancer Metastasis Rev1989;8:98-101

[2] Witz IP.The tumor microenvironment: the making of a paradigm.Cancer Microenviron2009;2 Suppl 1:9-17 PMCID:PMC2756342

[3] Fridlender ZG,Kim S.Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN.Cancer Cell2009;16:183-94 PMCID:PMC2754404

[4] Shaul ME.Tumour-associated neutrophils in patients with cancer.Nat Rev Clin Oncol2019;16:601-20

[5] Sheng Y,Huang Y.Tumor-activated neutrophils promote metastasis in breast cancer via the G-CSF-RLN2-MMP-9 axis.J Leukoc Biol2023;113:383-99

[6] Liu Y,Wang Y.c-Met mediated cytokine network promotes brain metastasis of breast cancer by remodeling neutrophil activities.Cancers2023;15:2626 PMCID:PMC10177081

[7] Tian S,Hu J.Tumour-associated neutrophils secrete AGR2 to promote colorectal cancer metastasis via its receptor CD98hc-xCT.Gut2022;71:2489-501

[8] Szczerba BM,Vetter M.Neutrophils escort circulating tumour cells to enable cell cycle progression.Nature2019;566:553-7

[9] Wang J,Hall MS.A synthetic metastatic niche reveals antitumor neutrophils drive breast cancer metastatic dormancy in the lungs.Nat Commun2023;14:4790 PMCID:PMC10409732

[10] Sagiv JY,Assi S.Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer.Cell Rep2015;10:562-73

[11] Anselmi M,Marzagalli M,Sommariva M.Melanoma stem cells educate neutrophils to support cancer progression.Cancers2022;14:3391 PMCID:PMC9317939

[12] Casbon AJ,Park C.Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils.Proc Natl Acad Sci U S A2015;112:E566-75 PMCID:PMC4330753

[13] Shang A,Wang W.Exosomal circPACRGL promotes progression of colorectal cancer via the miR-142-3p/miR-506-3p- TGF-β1 axis.Mol Cancer2020;19:117 PMCID:PMC7384220

[14] Andzinski L,Stahnke S.Type I IFNs induce anti-tumor polarization of tumor associated neutrophils in mice and human.Int J Cancer2016;138:1982-93

[15] Wang X,Li Z,Yi H.Understanding the multifaceted role of neutrophils in cancer and autoimmune diseases.Front Immunol2018;9:2456 PMCID:PMC6237929

[16] Ng MSF,Wang Q,Ng LG.Neutrophils in cancer-unresolved questions.Sci China Life Sci2021;64:1829-41

[17] Chen H,Pang L,Zhu Y.ANKRD22 is a potential novel target for reversing the immunosuppressive effects of PMN-MDSCs in ovarian cancer.J Immunother Cancer2023;11:e005527 PMCID:PMC9950970

[18] Yang L,Fukuda K.Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis.Cancer Cell2004;6:409-21

[19] Hu P,Zhang P.Intratumoral neutrophil granulocytes contribute to epithelial-mesenchymal transition in lung adenocarcinoma cells.Tumour Biol2015;36:7789-96

[20] Zhang W,Chen J.Interaction with neutrophils promotes gastric cancer cell migration and invasion by inducing epithelial-mesenchymal transition.Oncol Rep2017;38:2959-66

[21] Wang L,Zheng S,Cui P.miR-4780 derived from N2-Like neutrophil exosome aggravates epithelial-mesenchymal transition and angiogenesis in colorectal cancer.Stem Cells Int2023;2023:2759679 PMCID:PMC10421714

[22] Mayer C,Meyer AS.Neutrophil granulocytes in ovarian cancer - induction of epithelial-to-mesenchymal-transition and tumor cell migration.J Cancer2016;7:546-54 PMCID:PMC4820731

[23] Hu X,Feng Y.Neutrophils promote tumor progression in oral squamous cell carcinoma by regulating EMT and JAK2/STAT3 signaling through chemerin.Front Oncol2022;12:812044 PMCID:PMC8831747

[24] Wang Y,Zhang T.Neutrophils promote tumor invasion via FAM3C-mediated epithelial-to-mesenchymal transition in gastric cancer.Int J Biol Sci2023;19:1352-68 PMCID:PMC10086748

[25] Li S,Gao H.Tumor-associated neutrophils induce EMT by IL-17a to promote migration and invasion in gastric cancer cells.J Exp Clin Cancer Res2019;38:6 PMCID:PMC6323742

[26] Wang Y,Yang L.Tumor-contacted neutrophils promote metastasis by a CD90-TIMP-1 juxtacrine-paracrine loop.Clin Cancer Res2019;25:1957-69

[27] Liu X,Bauer AT.Neutrophils activated by membrane attack complexes increase the permeability of melanoma blood vessels.Proc Natl Acad Sci U S A2022;119:e2122716119 PMCID:PMC9388087

[28] Massagué J.Metastatic colonization by circulating tumour cells.Nature2016;529:298-306 PMCID:PMC5029466

[29] Chen MB,Benjamin DC.Inflamed neutrophils sequestered at entrapped tumor cells via chemotactic confinement promote tumor cell extravasation.Proc Natl Acad Sci U S A2018;115:7022-7 PMCID:PMC6142213

[30] Spiegel A,Houshyar S.Neutrophils suppress intraluminal NK cell-mediated tumor cell clearance and enhance extravasation of disseminated carcinoma cells.Cancer Discov2016;6:630-49 PMCID:PMC4918202

[31] McDowell SAC,Arabzadeh A.Neutrophil oxidative stress mediates obesity-associated vascular dysfunction and metastatic transmigration.Nat Cancer2021;2:545-62

[32] Spicer JD,Cools-Lartigue JJ.Neutrophils promote liver metastasis via Mac-1-mediated interactions with circulating tumor cells.Cancer Res2012;72:3919-27

[33] Yang M,Hou W.Negative effects of stromal neutrophils on T cells reduce survival in resectable urothelial carcinoma of the bladder.Front Immunol2022;13:827457 PMCID:PMC8978967

[34] Germann M,Sauvain MO.Neutrophils suppress tumor-infiltrating T cells in colon cancer via matrix metalloproteinase-mediated activation of TGFβ.EMBO Mol Med2020;12:e10681 PMCID:PMC6949488

[35] Güngör N,Munnia A.Genotoxic effects of neutrophils and hypochlorous acid.Mutagenesis2010;25:149-54

[36] Coffelt SB,Doornebal CW.IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis.Nature2015;522:345-8 PMCID:PMC4475637

[37] Romano A,Vetro C.The prognostic value of the myeloid-mediated immunosuppression marker Arginase-1 in classic Hodgkin lymphoma.Oncotarget2016;7:67333-46 PMCID:PMC5341879

[38] Wang TT,Peng LS.Tumour-activated neutrophils in gastric cancer foster immune suppression and disease progression through GM-CSF-PD-L1 pathway.Gut2017;66:1900-11 PMCID:PMC5739867

[39] Li P,Shi J.Dual roles of neutrophils in metastatic colonization are governed by the host NK cell status.Nat Commun2020;11:4387 PMCID:PMC7463263

[40] Markman JL,Wakita D.Loss of testosterone impairs anti-tumor neutrophil function.Nat Commun2020;11:1613 PMCID:PMC7109066

[41] Zhou SL,Hu ZQ.Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib.Gastroenterology2016;150:1646-1658.e17

[42] Xue R,Cao Q.Liver tumour immune microenvironment subtypes and neutrophil heterogeneity.Nature2022;612:141-7

[43] Kaplan RN,Zacharoulis S.VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche.Nature2005;438:820-7 PMCID:PMC2945882

[44] Wculek SK.Neutrophils support lung colonization of metastasis-initiating breast cancer cells.Nature2015;528:413-7 PMCID:PMC4700594

[45] Liu Y,Han Y.Tumor exosomal RNAs promote lung pre-metastatic niche formation by activating alveolar epithelial TLR3 to recruit neutrophils.Cancer Cell2016;30:243-56

[46] Zheng Z,Jia S.Lung mesenchymal stromal cells influenced by Th2 cytokines mobilize neutrophils and facilitate metastasis by producing complement C3.Nat Commun2021;12:6202 PMCID:PMC8551331

[47] Carnevale S,Rigatelli A.The complexity of neutrophils in health and disease: focus on cancer.Semin Immunol2020;48:101409 PMCID:PMC7500440

[48] Piccard H,Opdenakker G.On the dual roles and polarized phenotypes of neutrophils in tumor development and progression.Crit Rev Oncol Hematol2012;82:296-309

[49] Kowanetz M,Lee J.Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes.Proc Natl Acad Sci U S A2010;107:21248-55 PMCID:PMC3003076

[50] Brinkmann V,Goosmann C.Neutrophil extracellular traps kill bacteria.Science2004;303:1532-5

[51] Park J,Amoozgar Z.Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps.Sci Transl Med2016;8:361ra138 PMCID:PMC5550900

[52] Jiang ZZ,Liu XC.Neutrophil extracellular traps induce tumor metastasis through dual effects on cancer and endothelial cells.Oncoimmunology2022;11:2052418 PMCID:PMC8928819

[53] Teijeira Á,Gato M.CXCR1 and CXCR2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity.Immunity2020;52:856-871.e8

[54] Najmeh S,Rayes RF.Neutrophil extracellular traps sequester circulating tumor cells via β1-integrin mediated interactions.Int J Cancer2017;140:2321-30

[55] Yang L,Zhang X.DNA of neutrophil extracellular traps promotes cancer metastasis via CCDC25.Nature2020;583:133-8

[56] Stehr AM,Demmler R.Neutrophil extracellular traps drive epithelial-mesenchymal transition of human colon cancer.J Pathol2022;256:455-67

[57] Martins-Cardoso K,Bagri KM.Neutrophil extracellular traps (NETs) promote pro-metastatic phenotype in human breast cancer cells through epithelial-mesenchymal transition.Cancers2020;12:1542 PMCID:PMC7352979

[58] Zhu T,Yang C.Neutrophil extracellular traps promote gastric cancer metastasis by inducing epithelial‑mesenchymal transition.Int J Mol Med2021;48:127 PMCID:PMC8128417

[59] Jin W,Li H,Xu HX.Neutrophil extracellular DNA traps promote pancreatic cancer cells migration and invasion by activating EGFR/ERK pathway.J Cell Mol Med2021;25:5443-56 PMCID:PMC8184670

[60] Lee W,Mohamed MS,Lengyel E.Neutrophils facilitate ovarian cancer premetastatic niche formation in the omentum.J Exp Med2019;216:176-94 PMCID:PMC6314534

[61] Kanamaru R,Miyato H.Low density neutrophils (LDN) in postoperative abdominal cavity assist the peritoneal recurrence through the production of neutrophil extracellular traps (NETs).Sci Rep2018;8:632 PMCID:PMC5766579

[62] Yang L,Zhang R.IL-8 mediates a positive loop connecting increased neutrophil extracellular traps (NETs) and colorectal cancer liver metastasis.J Cancer2020;11:4384-96 PMCID:PMC7255375

[63] Kaltenmeier C,Morder K,Simmons RL.Neutrophil extracellular traps promote t cell exhaustion in the tumor microenvironment.Front Immunol2021;12:785222 PMCID:PMC8652262

[64] Orditura M,Diana A.Neutrophil to lymphocyte ratio (NLR) for prediction of distant metastasis-free survival (DMFS) in early breast cancer: a propensity score-matched analysis.ESMO Open2016;1:e000038 PMCID:PMC5070254

[65] Ethier JL,Templeton A,Amir E.Prognostic role of neutrophil-to-lymphocyte ratio in breast cancer: a systematic review and meta-analysis.Breast Cancer Res2017;19:2 PMCID:PMC5217326

[66] Romano A,Vetro C.Prognostic meaning of neutrophil to lymphocyte ratio (NLR) and lymphocyte to monocyte ration (LMR) in newly diagnosed Hodgkin lymphoma patients treated upfront with a PET-2 based strategy.Ann Hematol2018;97:1009-18

[67] García-Ortega DY,Alvarez-Cano A.Neutrophil-to-Lymphocyte ratio as a prognostic biomarker in extremities undifferentiated pleomorphic sarcoma.Surg Oncol2022;42:101746

[68] Fausti V,Vanni S.Systemic inflammatory indices in second-line soft tissue sarcoma patients: focus on lymphocyte/monocyte ratio and trabectedin.Cancers2023;15:1080 PMCID:PMC9954182

[69] Wang W,Sun S.Predictive value of NLR and PLR in response to preoperative chemotherapy and prognosis in locally advanced gastric cancer.Front Oncol2022;12:936206 PMCID:PMC9468320

[70] Tokumaru Y,Murthy V.Low intratumoral genetic neutrophil-to-lymphocyte ratio (NLR) is associated with favorable tumor immune microenvironment and with survival in triple negative breast cancer (TNBC).Am J Cancer Res2021;11:5743-55 PMCID:PMC8640806

[71] Li Y,Wang X,Ren M.The prognostic utility of preoperative neutrophil-to-lymphocyte ratio (NLR) in patients with colorectal liver metastasis: a systematic review and meta-analysis.Cancer Cell Int2023;23:39 PMCID:PMC9976405

[72] Maloney S,Itchins M.The prognostic and predictive role of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) as biomarkers in resected pancreatic cancer.J Clin Med2023;12:1989 PMCID:PMC10004269

[73] Gambardella C,Paolicelli M.Role of inflammatory biomarkers (NLR, LMR, PLR) in the prognostication of malignancy in indeterminate thyroid nodules.Int J Mol Sci2023;24:6466 PMCID:PMC10094849

[74] Zhang CL,Li Y.Independent predictive value of blood inflammatory composite markers in ovarian cancer: recent clinical evidence and perspective focusing on NLR and PLR.J Ovarian Res2023;16:36 PMCID:PMC9912515

[75] Griffiths TT,Smith IM.The baseline neutrophil lymphocyte ratio predicts survival in soft-tissue sarcoma: a 17-year cohort study.J Plast Reconstr Aesthet Surg2022;75:1372-9

[76] Koseci T,Olgun P.Prognostic importance of inflammatory indexes in patients treated by pazopanib for soft tissue sarcoma.Clin Lab2022;68

[77] Vanni S,Fonzi E.Unveiling the genomic basis of chemosensitivity in sarcomas of the extremities: an integrated approach for an unmet clinical need.Int J Mol Sci2023;24:6926 PMCID:PMC10138892

[78] Koh YW,Ahn MS,Lee HW.Baseline neutrophil-lymphocyte ratio is associated with baseline and subsequent presence of brain metastases in advanced non-small-cell lung cancer.Sci Rep2016;6:38585 PMCID:PMC5141478

[79] Peng J,Ou Q.Preoperative lymphocyte-to-monocyte ratio represents a superior predictor compared with neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios for colorectal liver-only metastases survival.Onco Targets Ther2017;10:3789-99 PMCID:PMC5538703

[80] Ye Z,Cao Y.Prediction of peritoneal cancer index and prognosis in peritoneal metastasis of gastric cancer using NLR-PLR-DDI score: a retrospective study.Cancer Manag Res2022;14:177-87 PMCID:PMC8763204

[81] Hu J,He T.A nomogram incorporating PD-L1, NLR, and clinicopathologic features to predict inguinal lymph node metastasis in penile squamous cell carcinoma.Urol Oncol2020;38:641.e19-29

[82] Faget J,Quantin X,Bonnefoy N.Neutrophils in the era of immune checkpoint blockade.J Immunother Cancer2021;9:e002242 PMCID:PMC8728357

[83] Ocana A,Pandiella A.Neutrophils in cancer: prognostic role and therapeutic strategies.Mol Cancer2017;16:137 PMCID:PMC5558711

[84] Lin ZQ,Cao WZ,Tan G.Prognostic significance of NLR, PLR, LMR and tumor infiltrating t lymphocytes in patients undergoing surgical resection for hilar cholangiocarcinoma.Front Oncol2022;12:908907 PMCID:PMC9203898

[85] Li M,Burkart J.Change in neutrophil to lymphocyte ratio during immunotherapy treatment is a non-linear predictor of patient outcomes in advanced cancers.J Cancer Res Clin Oncol2019;145:2541-6 PMCID:PMC6751277

[86] He G,Zhou J.Peritumoural neutrophils negatively regulate adaptive immunity via the PD-L1/PD-1 signalling pathway in hepatocellular carcinoma.J Exp Clin Cancer Res2015;34:141 PMCID:PMC4652417

[87] Li K,Gai J.Multi-omic analyses of changes in the tumor microenvironment of pancreatic adenocarcinoma following neoadjuvant treatment with anti-PD-1 therapy.Cancer Cell2022;40:1374-1391.e7 PMCID:PMC9669212

[88] Krieg C,Guglietta S.High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy.Nat Med2018;24:144-53

[89] Schott AF,Cristofanilli M.Phase Ib pilot study to evaluate reparixin in combination with weekly paclitaxel in patients with HER-2-negative metastatic breast cancer.Clin Cancer Res2017;23:5358-65 PMCID:PMC5600824

[90] Brandes AA,Kesari S.A phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma.Neuro Oncol2016;18:1146-56 PMCID:PMC4933481

[91] Melisi D,Hollebecque A.Safety and activity of the TGFβ receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer.J Immunother Cancer2021;9:e002068 PMCID:PMC7944986

[92] Faivre S,Kelley RK.Novel transforming growth factor beta receptor I kinase inhibitor galunisertib (LY2157299) in advanced hepatocellular carcinoma.Liver Int2019;39:1468-77

[93] Nadal E,Aix SP.A phase Ib/II study of galunisertib in combination with nivolumab in solid tumors and non-small cell lung cancer.BMC Cancer2023;23:708 PMCID:PMC10386782

[94] Yamazaki T,Gilchrist M.Galunisertib plus neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: a single-arm, phase 2 trial.Lancet Oncol2022;23:1189-200

[95] Powell D,Barros Becker F.Cxcr1 mediates recruitment of neutrophils and supports proliferation of tumor-initiating astrocytes in vivo.Sci Rep2018;8:13285 PMCID:PMC6125480

[96] Sharma B,Nannuru KC,Singh RK.Targeting CXCR2 enhances chemotherapeutic response, inhibits mammary tumor growth, angiogenesis, and lung metastasis.Mol Cancer Ther2013;12:799-808 PMCID:PMC3653628

[97] Du M,Gruslin A.SB225002 promotes mitotic catastrophe in chemo-sensitive and -resistant ovarian cancer cells independent of p53 status in vitro.PLoS One2013;8:e54572 PMCID:PMC3554720

[98] Yang L,Wu R,Gu Z.Correlation of C-X-C chemokine receptor 2 upregulation with poor prognosis and recurrence in human glioma.Onco Targets Ther2015;8:3203-9 PMCID:PMC4636088

[99] Lu X,Paul E.Erratum: effective combinatorial immunotherapy for castration-resistant prostate cancer.Nature2017;545:116

[100] Sun L,Robbins Y.Inhibiting myeloid-derived suppressor cell trafficking enhances T cell immunotherapy.JCI Insight2019;4:126853 PMCID:PMC6483637

[101] Dominguez GA,Mony S.Selective Targeting of Myeloid-Derived Suppressor Cells in Cancer Patients Using DS-8273a, an Agonistic TRAIL-R2 Antibody.Clin Cancer Res2017;23:2942-50 PMCID:PMC5468499

[102] Condamine T,Ramachandran IR.ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis.J Clin Invest2014;124:2626-39 PMCID:PMC4038578

[103] Chen M,Wang S.Neutrophils as emerging immunotherapeutic targets: Indirect treatment of tumors by regulating the tumor immune environment based on a sialic acid derivative-modified nanocomplex platform.Int J Pharm2022;620:121684

[104] Tian S,Piao L.Del-1 enhances therapeutic efficacy of bacterial cancer immunotherapy by blocking recruitment of tumor-infiltrating neutrophils.Clin Transl Oncol2022;24:244-53

[105] Wang Y,Zhao B.Remodeling tumor-associated neutrophils to enhance dendritic cell-based hcc neoantigen nano-vaccine efficiency.Adv Sci2022;9:e2105631 PMCID:PMC9009112

[106] Sionov RV.Leveling up the controversial role of neutrophils in cancer: when the complexity becomes entangled.Cells2021;10:2486 PMCID:PMC8465406

[107] Tyagi A,Sharma S.Exosomal miR-4466 from nicotine-activated neutrophils promotes tumor cell stemness and metabolism in lung cancer metastasis.Oncogene2022;41:3079-92 PMCID:PMC9135627

[108] Peng H,Long X.Local release of TGF-β inhibitor modulates tumor-associated neutrophils and enhances pancreatic cancer response to combined irreversible electroporation and immunotherapy.Adv Sci2022;9:e2105240 PMCID:PMC8981446

[109] Qin F,Chen J.Anti-TGF-β attenuates tumor growth via polarization of tumor associated neutrophils towards an anti-tumor phenotype in colorectal cancer.J Cancer2020;11:2580-92 PMCID:PMC7066015

[110] Rodon J,Sepulveda-Sánchez JM.First-in-human dose study of the novel transforming growth factor-β receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma.Clin Cancer Res2015;21:553-60 PMCID:PMC4337847

[111] Jablonska J,Westphal K,Weiss S.Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model.J Clin Invest2010;120:1151-64 PMCID:PMC2846036

[112] Alekseeva LA,Zenkova MA.Targeting circulating SINEs and LINEs with DNase I provides metastases inhibition in experimental tumor models.Mol Ther Nucleic Acids2020;20:50-61 PMCID:PMC7058713

[113] Hsu BE,Johnson RM.Immature low-density neutrophils exhibit metabolic flexibility that facilitates breast cancer liver metastasis.Cell Rep2019;27:3902-3915.e6

[114] Wang Z,Li L.Tumor-derived HMGB1 induces CD62L(dim) neutrophil polarization and promotes lung metastasis in triple-negative breast cancer.Oncogenesis2020;9:82 PMCID:PMC7499196

[115] Boone BA,Schapiro NE.The receptor for advanced glycation end products (RAGE) enhances autophagy and neutrophil extracellular traps in pancreatic cancer.Cancer Gene Ther2015;22:326-34 PMCID:PMC4470814

[116] Cook KL,Soto-Pantoja DR.Hydroxychloroquine inhibits autophagy to potentiate antiestrogen responsiveness in ER+ breast cancer.Clin Cancer Res2014;20:3222-32 PMCID:PMC4073207

[117] Bruni D,Galon J.The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy.Nat Rev Cancer2020;20:662-80

[118] Bullock K.Suppressing MDSC recruitment to the tumor microenvironment by antagonizing CXCR2 to enhance the efficacy of immunotherapy.Cancers2021;13:6293 PMCID:PMC8699249

[119] Steele CW,Leach JDG.CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma.Cancer Cell2016;29:832-45 PMCID:PMC4912354

[120] Highfill SL,Giles AJ.Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy.Sci Transl Med2014;6:237ra67 PMCID:PMC6980372

[121] Nielsen SR,Horton ER.Suppression of tumor-associated neutrophils by lorlatinib attenuates pancreatic cancer growth and improves treatment with immune checkpoint blockade.Nat Commun2021;12:3414 PMCID:PMC8184753

[122] Bergerot P,Wang E.Cabozantinib in combination with immunotherapy for advanced renal cell carcinoma and urothelial carcinoma: rationale and clinical evidence.Mol Cancer Ther2019;18:2185-93

[123] Cheng Y,Li Q.Targeting CXCR2 inhibits the progression of lung cancer and promotes therapeutic effect of cisplatin.Mol Cancer2021;20:62 PMCID:PMC8019513

[124] Fang Y,Jiang Y.Blocking TGF-β expression attenuates tumor growth in lung cancers, potentially mediated by skewing development of neutrophils.J Oncol2022;2022:3447185 PMCID:PMC9050332

[125] Schedel F,Pappelbaum KI.Evidence and impact of neutrophil extracellular traps in malignant melanoma.Pigment Cell Melanoma Res2020;33:63-73

[126] Arelaki S,Kambas K.Gradient infiltration of neutrophil extracellular traps in colon cancer and evidence for their involvement in tumour growth.PLoS One2016;11:e0154484 PMCID:PMC4852909