{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T19:22:39Z","timestamp":1792264959486,"version":"4.4.0"},"reference-count":98,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,17]],"date-time":"2022-02-17T00:00:00Z","timestamp":1645056000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Brain metastasis (BM), a devastating complication of advanced malignancy, has a high incidence in non-small cell lung cancer (NSCLC). As novel systemic treatment drugs and improved, more sensitive imaging investigations are performed, more patients will be diagnosed with BM. However, the main treatment methods face a high risk of complications at present. Therefore, based on immunotherapy of tumor immune microenvironment has been proposed. The development of NSCLC and its BM is closely related to the tumor microenvironment, the surrounding microenvironment where tumor cells live. In the event of BM, the metastatic tumor microenvironment in BM is composed of extracellular matrix, tissue-resident cells that change with tumor colonization and blood-derived immune cells. Immune-related cells and chemicals in the NSCLC brain metastasis microenvironment are targeted by BM immunotherapy, with immune checkpoint inhibition therapy being the most important. Blocking cancer immunosuppression by targeting immune checkpoints provides a suitable strategy for immunotherapy in patients with advanced cancers. In the past few years, several therapeutic advances in immunotherapy have changed the outlook for the treatment of BM from NSCLC. According to emerging evidence, immunotherapy plays an essential role in treating BM, with a more significant safety profile than others. This article discusses recent advances in the biology of BM from NSCLC, reviews novel mechanisms in diverse tumor metastatic stages, and emphasizes the role of the tumor immune microenvironment in metastasis. In addition, clinical advances in immunotherapy for this disease are mentioned.<\/jats:p>","DOI":"10.3389\/fimmu.2022.829451","type":"journal-article","created":{"date-parts":[[2022,2,17]],"date-time":"2022-02-17T00:32:23Z","timestamp":1645057943000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":65,"title":["Tumor Immune Microenvironment and Immunotherapy in Brain Metastasis From Non-Small Cell Lung Cancer"],"prefix":"10.3389","volume":"13","author":[{"given":"Yuchang","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shikuan","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijian","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junbo","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gelei","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/noajnl\/vdaa041","article-title":"Epidemiology of Synchronous Brain Metastases","volume":"2","author":"Singh","year":"2020","journal-title":"Neuro-Oncol Adv"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2019.2996","article-title":"Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2017: A Systematic Analysis for the Global Burden of Disease Study","volume":"5","author":"Fitzmaurice","year":"2019","journal-title":"JAMA Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noaa233","article-title":"Population-Based Estimates of Survival Among Elderly Patients With Brain Metastases","volume":"23","author":"Lamba","year":"2020","journal-title":"Neuro-Oncology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21654","article-title":"Cancer Statistics, 2021","volume":"71","author":"Siegel","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"B5","doi-asserted-by":"publisher","first-page":"299","DOI":"10.3322\/caac.21671","article-title":"Racial and Socioeconomic Disparities in Lung Cancer Screening in the United States: A Systematic Review","volume":"71","author":"Sosa","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"B7","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.lungcan.2021.02.031","article-title":"Efficacy and Safety of Treatment Modalities Across EGFR Selected\/Unselected Populations With Non-Small Cell Lung Cancer and Brain Metastases: A Systematic Review and Bayesian Network Meta-Analysis","volume":"158","author":"Liu","year":"2021","journal-title":"Lung Cancer (Amsterdam Netherlands)"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-018-0055-y","article-title":"Brain Metastases","volume":"5","author":"Achrol","year":"2019","journal-title":"Nat Rev Dis Primers"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2012.08.007","article-title":"Use of Stereotactic Radiosurgery for Brain Metastases From Non-Small Cell Lung Cancer in the United States","volume":"85","author":"Halasz","year":"2013","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B10","doi-asserted-by":"publisher","first-page":"17","DOI":"10.3171\/2015.6.Jns142763","article-title":"Does Immunotherapy Increase the Rate of Radiation Necrosis After Radiosurgical Treatment of Brain Metastases","volume":"125","author":"Colaco","year":"2016","journal-title":"J Neurosurg"},{"key":"B11","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1038\/s41568-019-0220-y","article-title":"Brain Metastasis","volume":"20","author":"Boire","year":"2020","journal-title":"Nat Rev Cancer"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1007\/s10585-012-9457-5","article-title":"Tumor Microenvironment: A Main Actor in the Metastasis Process","volume":"29","author":"Spano","year":"2012","journal-title":"Clin Exp Metastasis"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2020.102067","article-title":"Immunotherapy in NSCLC Patients With Brain Metastases. Understanding Brain Tumor Microenvironment and Dissecting Outcomes From Immune Checkpoint Blockade in the Clinic","volume":"89","author":"Vilari\u00f1o","year":"2020","journal-title":"Cancer Treat Rev"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1801005","article-title":"Pembrolizumab Plus Chemotherapy in Metastatic Non\u2013Small-Cell Lung Cancer","volume":"378","author":"Gandhi","year":"2018","journal-title":"New Engl J Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.577159","article-title":"Response of Pembrolizumab Alone for Non-Small Cell Lung Cancer With Brain Metastasis: A Case Report and Literature Review","volume":"10","author":"Marvin","year":"2020","journal-title":"Front Oncol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1038\/s41568-019-0205-x","article-title":"The Blood-Brain Barrier and Blood-Tumour Barrier in Brain Tumours and Metastases","volume":"20","author":"Arvanitis","year":"2020","journal-title":"Nat Rev Cancer"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.2174\/157015908785777210","article-title":"Brain Endothelial Cell-Cell Junctions: How to \u201cOpen\u201d the Blood Brain Barrier","volume":"6","author":"Stamatovic","year":"2008","journal-title":"Curr Neuropharmacol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-018-1806-2","article-title":"T Lymphocytes Facilitate Brain Metastasis of Breast Cancer by Inducing Guanylate-Binding Protein 1 Expression","volume":"135","author":"Mustafa","year":"2018","journal-title":"Acta Neuropathol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X16655551","article-title":"Matrix Metalloproteinases in the Brain and Blood-Brain Barrier: Versatile Breakers and Makers","volume":"36","author":"Rempe","year":"2016","journal-title":"J Cereb Blood Flow Metab"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.602185","article-title":"Roles of the Cyclooxygenase 2 Matrix Metalloproteinase 1 Pathway in Brain Metastasis of Breast Cancer","volume":"290","author":"Wu","year":"2015","journal-title":"J Biol Chem"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22518","article-title":"Carcinoma Cells Misuse the Host Tissue Damage Response to Invade the Brain","volume":"61","author":"Chuang","year":"2013","journal-title":"Glia"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-018-1389-9","article-title":"Long-Term Characterization of Activated Microglia\/Macrophages Facilitating the Development of Experimental Brain Metastasis Through Intravital Microscopic Imaging","volume":"16","author":"Qiao","year":"2019","journal-title":"J Neuroinflamm"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/S1072-7515(00)00250-7","article-title":"Sir James Paget (1814-1889): A Great Academic Victorian","volume":"191","author":"Coppes-Zantinga","year":"2000","journal-title":"J Am Coll Surg"},{"key":"B24","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.molmed.2008.03.004","article-title":"Epithelial-Mesenchymal Transition and the Invasive Potential of Tumors","volume":"14","author":"Gavert","year":"2008","journal-title":"Trends Mol Med"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2019.109320","article-title":"Aberrant N-Cadherin Expression in Cancer","volume":"118","author":"Cao","year":"2019","journal-title":"BioMed Pharmacother"},{"key":"B26","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.canlet.2021.08.025","article-title":"ZIP4 Promotes Non-Small Cell Lung Cancer Metastasis by Activating Snail-N-Cadherin Signaling Axis","volume":"521","author":"Jiang","year":"2021","journal-title":"Cancer Lett"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12092402","article-title":"Midkine Is a Potential Therapeutic Target of Tumorigenesis, Angiogenesis, and Metastasis in Non-Small Cell Lung Cancer","volume":"12","author":"Shin","year":"2020","journal-title":"Cancers"},{"key":"B28","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/tpj.2015.86","article-title":"Genetic Variants Associated With Colorectal Brain Metastases Susceptibility and Survival","volume":"17","author":"Stremitzer","year":"2017","journal-title":"Pharmacogenom J"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2012.193342","article-title":"The Biology of Brain Metastasis","volume":"59","author":"Langley","year":"2013","journal-title":"Clin Chem"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.14156","article-title":"Paracellular and Transcellular Migration of Metastatic Cells Through the Cerebral Endothelium","volume":"23","author":"Herman","year":"2019","journal-title":"J Cell Mol Med"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.07.001","article-title":"Intravascular Survival and Extravasation of Tumor Cells","volume":"32","author":"Strilic","year":"2017","journal-title":"Cancer Cell"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1474","DOI":"10.3390\/ijms18071474","article-title":"CD15s\/CD62E Interaction Mediates the Adhesion of Non-Small Cell Lung Cancer Cells on Brain Endothelial Cells: Implications for Cerebral Metastasis","volume":"18","author":"Jassam","year":"2017","journal-title":"Int J Mol Sci"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/nov248","article-title":"TNF-\u03b1 Enhancement of CD62E Mediates Adhesion of Non-Small Cell Lung Cancer Cells to Brain Endothelium via CD15 in Lung-Brain Metastasis","volume":"18","author":"Jassam","year":"2016","journal-title":"Neuro Oncol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-019-03188-x","article-title":"Fucosyltransferase 4 and 7 Mediates Adhesion of Non-Small Cell Lung Cancer Cells to Brain-Derived Endothelial Cells and Results in Modification of the Blood-Brain-Barrier: In Vitro Investigation of CD15 and CD15s in Lung-to-Brain Metastasis","volume":"143","author":"Jassam","year":"2019","journal-title":"J Neurooncol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1007\/s00432-018-2761-y","article-title":"FUT4 is Involved in PD-1-Related Immunosuppression and Leads to Worse Survival in Patients With Operable Lung Adenocarcinoma","volume":"145","author":"Liu","year":"2019","journal-title":"J Cancer Res Clin Oncol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/nature08021","article-title":"Genes That Mediate Breast Cancer Metastasis to the Brain","volume":"459","author":"Bos","year":"2009","journal-title":"Nature"},{"key":"B37","doi-asserted-by":"publisher","first-page":"6716","DOI":"10.1038\/ncomms7716","article-title":"Brain Metastatic Cancer Cells Release microRNA-181c-Containing Extracellular Vesicles Capable of Destructing Blood-Brain Barrier","volume":"6","author":"Tominaga","year":"2015","journal-title":"Nat Commun"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab012","article-title":"Emerging Principles of Brain Immunology and Immune Checkpoint Blockade in Brain Metastases","volume":"144","author":"Fares","year":"2021","journal-title":"Brain"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.02.009","article-title":"The Microenvironmental Landscape of Brain Tumors","volume":"31","author":"Quail","year":"2017","journal-title":"Cancer Cell"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/nature14432","article-title":"Structural and Functional Features of Central Nervous System Lymphatic Vessels","volume":"523","author":"Louveau","year":"2015","journal-title":"Nature"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/ni1178","article-title":"Naturally Arising Foxp3-Expressing CD25+CD4+ Regulatory T Cells in Immunological Tolerance to Self and Non-Self","volume":"6","author":"Sakaguchi","year":"2005","journal-title":"Nat Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2849","article-title":"Costimulation via the Tumor-Necrosis Factor Receptor Superfamily Couples TCR Signal Strength to the Thymic Differentiation of Regulatory T Cells","volume":"15","author":"Mahmud","year":"2014","journal-title":"Nat Immunol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/s41590-018-0289-6","article-title":"Thymic Regulatory T Cells Arise via Two Distinct Developmental Programs","volume":"20","author":"Owen","year":"2019","journal-title":"Nat Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2016.151","article-title":"Regulatory T Cells in Cancer Immunotherapy","volume":"27","author":"Tanaka","year":"2017","journal-title":"Cell Res"},{"key":"B45","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/s12885-018-5214-8","article-title":"Differences in Tumor Microenvironments Between Primary Lung Tumors and Brain Metastases in Lung Cancer Patients: Therapeutic Implications for Immune Checkpoint Inhibitors","volume":"19","author":"Kim","year":"2019","journal-title":"BMC Cancer"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtocrr.2021.100230","article-title":"Comparison of Tumor Microenvironments Between Primary Tumors and Brain Metastases in Patients With NSCLC","volume":"2","author":"Ikarashi","year":"2021","journal-title":"JTO Clin Res Rep"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz207","article-title":"Suppressed Immune Microenvironment and Repertoire in Brain Metastases From Patients With Resected Non-Small-Cell Lung Cancer","volume":"30","author":"Kudo","year":"2019","journal-title":"Ann Oncol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201847659","article-title":"Targeting Treg Cells in Cancer Immunotherapy","volume":"49","author":"Tanaka","year":"2019","journal-title":"Eur J Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.Cd-18-0367","article-title":"Fundamental Mechanisms of Immune Checkpoint Blockade Therapy","volume":"8","author":"Wei","year":"2018","journal-title":"Cancer Discov"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(16)00587-0","article-title":"Atezolizumab Versus Docetaxel for Patients With Previously Treated Non-Small-Cell Lung Cancer (POPLAR): A Multicentre, Open-Label, Phase 2 Randomised Controlled Trial","volume":"387","author":"Fehrenbacher","year":"2016","journal-title":"Lancet"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1514296","article-title":"Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway","volume":"375","author":"Boussiotis","year":"2016","journal-title":"N Engl J Med"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-019-02384-y","article-title":"Tumor-Induced Peripheral Immunosuppression Promotes Brain Metastasis in Patients With Non-Small Cell Lung Cancer","volume":"68","author":"Li","year":"2019","journal-title":"Cancer Immunol Immunother"},{"key":"B53","doi-asserted-by":"publisher","first-page":"S66","DOI":"10.21037\/atm.2018.10.27","article-title":"The Risk Factors for Brain Metastases in Patients With Non-Small Cell Lung Cancer","volume":"6","author":"Lim","year":"2018","journal-title":"Ann Transl Med"},{"key":"B54","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.intimp.2018.06.001","article-title":"Immune Checkpoint Blockade Therapy for Cancer: An Overview of FDA-Approved Immune Checkpoint Inhibitors","volume":"62","author":"Hargadon","year":"2018","journal-title":"Int Immunopharmacol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2019.09.030","article-title":"Mechanisms Controlling PD-L1 Expression in Cancer","volume":"76","author":"Cha","year":"2019","journal-title":"Mol Cell"},{"key":"B56","doi-asserted-by":"publisher","first-page":"e002230","DOI":"10.1136\/jitc-2020-002230","article-title":"Comparison of Programmed Death-Ligand 1 Protein Expression Between Primary and Metastatic Lesions in Patients With Lung Cancer","volume":"9","author":"Moutafi","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2020.04.018","article-title":"Programmed Death Receptor Ligand One Expression May Independently Predict Survival in Patients With Non-Small Cell Lung Carcinoma Brain Metastases Receiving Immunotherapy","volume":"108","author":"Hulsbergen","year":"2020","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(20)30111-x","article-title":"Pembrolizumab for Management of Patients With NSCLC and Brain Metastases: Long-Term Results and Biomarker Analysis From a Non-Randomised, Open-Label, Phase 2 Trial","volume":"21","author":"Goldberg","year":"2020","journal-title":"Lancet Oncol"},{"key":"B59","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/nrclinonc.2016.217","article-title":"Tumour-Associated Macrophages as Treatment Targets in Oncology","volume":"14","author":"Mantovani","year":"2017","journal-title":"Nat Rev Clin Oncol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4185","article-title":"The Role of Microglia and Macrophages in Glioma Maintenance and Progression","volume":"19","author":"Hambardzumyan","year":"2016","journal-title":"Nat Neurosci"},{"key":"B61","doi-asserted-by":"publisher","first-page":"1643","DOI":"10.1016\/j.cell.2020.05.007","article-title":"Interrogation of the Microenvironmental Landscape in Brain Tumors Reveals Disease-Specific Alterations of Immune Cells","volume":"181","author":"Klemm","year":"2020","journal-title":"Cell"},{"key":"B62","doi-asserted-by":"publisher","first-page":"e11210","DOI":"10.15252\/emmm.201911210","article-title":"Glufosinate Constrains Synchronous and Metachronous Metastasis by Promoting Anti-Tumor Macrophages","volume":"12","author":"Menga","year":"2020","journal-title":"EMBO Mol Med"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioactmat.2020.12.010","article-title":"The Application of Nanoparticles in Cancer Immunotherapy: Targeting Tumor Microenvironment","volume":"6","author":"Yang","year":"2021","journal-title":"Bioact Mater"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1080\/15384101.2018.1444305","article-title":"Tumor-Derived Lactate Induces M2 Macrophage Polarization via the Activation of the ERK\/STAT3 Signaling Pathway in Breast Cancer","volume":"17","author":"Mu","year":"2018","journal-title":"Cell Cycle"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-020-02840-0","article-title":"Comparative Analysis of the Tumor Immune-Microenvironment of Primary and Brain Metastases of Non-Small-Cell Lung Cancer Reveals Organ-Specific and EGFR Mutation-Dependent Unique Immune Landscape","volume":"70","author":"Song","year":"2021","journal-title":"Cancer Immunol Immunother"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.neo.2021.09.001","article-title":"In Vivo Two-Photon Characterization of Tumor-Associated Macrophages and Microglia (TAM\/M) and CX3CR1 During Different Steps of Brain Metastasis Formation From Lung Cancer","volume":"23","author":"Zhang","year":"2021","journal-title":"Neoplasia"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2020.101178","article-title":"Cellular and Molecular Changes of Brain Metastases-Associated Myeloid Cells During Disease Progression and Therapeutic Response","volume":"23","author":"Schulz","year":"2020","journal-title":"iScience"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.021908.132528","article-title":"Microglial Physiology: Unique Stimuli, Specialized Responses","volume":"27","author":"Ransohoff","year":"2009","journal-title":"Annu Rev Immunol"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2009.06253.x","article-title":"Fractalkine-Induced Activation of the Phosphatidylinositol-3 Kinase Pathway Attentuates Microglial Activation In Vivo and In Vitro","volume":"110","author":"Lyons","year":"2009","journal-title":"J Neurochem"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00049","article-title":"Targeting Macrophages in Cancer: From Bench to Bedside","volume":"8","author":"Poh","year":"2018","journal-title":"Front Oncol"},{"key":"B71","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1007\/s00401-009-0619-8","article-title":"Astrocytes: Biology and Pathology","volume":"119","author":"Sofroniew","year":"2010","journal-title":"Acta Neuropathol"},{"key":"B72","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1007\/s10585-010-9354-8","article-title":"Interaction Between Lung Cancer Cells and Astrocytes via Specific Inflammatory Cytokines in the Microenvironment of Brain Metastasis","volume":"28","author":"Seike","year":"2011","journal-title":"Clin Exp Metastasis"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.01.040","article-title":"Serpins Promote Cancer Cell Survival and Vascular Co-Option in Brain Metastasis","volume":"156","author":"Valiente","year":"2014","journal-title":"Cell"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1038\/nature18268","article-title":"Carcinoma-Astrocyte Gap Junctions Promote Brain Metastasis by cGAMP Transfer","volume":"533","author":"Chen","year":"2016","journal-title":"Nature"},{"key":"B75","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1038\/s41467-017-00983-w","article-title":"TRPA1-FGFR2 Binding Event is a Regulatory Oncogenic Driver Modulated by miRNA-142-3p","volume":"8","author":"Berrout","year":"2017","journal-title":"Nat Commun"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1038\/nature15376","article-title":"Microenvironment-Induced PTEN Loss by Exosomal microRNA Primes Brain Metastasis Outgrowth","volume":"527","author":"Zhang","year":"2015","journal-title":"Nature"},{"key":"B77","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1186\/s12943-019-1019-x","article-title":"CAFs Secreted Exosomes Promote Metastasis and Chemotherapy Resistance by Enhancing Cell Stemness and Epithelial-Mesenchymal Transition in Colorectal Cancer","volume":"18","author":"Hu","year":"2019","journal-title":"Mol Cancer"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01835","article-title":"The Dark Side of Fibroblasts: Cancer-Associated Fibroblasts as Mediators of Immunosuppression in the Tumor Microenvironment","volume":"10","author":"Monteran","year":"2019","journal-title":"Front Immunol"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.Cir-14-0002","article-title":"The Carcinoma-Associated Fibroblast Expressing Fibroblast Activation Protein and Escape From Immune Surveillance","volume":"2","author":"Fearon","year":"2014","journal-title":"Cancer Immunol Res"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-15-0369","article-title":"Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets","volume":"5","author":"Brastianos","year":"2015","journal-title":"Cancer Discovery"},{"key":"B81","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.ccr.2009.12.020","article-title":"Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1","volume":"17","author":"Verhaak","year":"2010","journal-title":"Cancer Cell"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.691811","article-title":"Immune Infiltrating Cells-Derived Risk Signature Based on Large-Scale Analysis Defines Immune Landscape and Predicts Immunotherapy Responses in Glioma Tumor Microenvironment","volume":"12","author":"Zhang","year":"2021","journal-title":"Front Immunol"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.2806","article-title":"First-Line Pembrolizumab for Non-Small Cell Lung Cancer Patients With PD-L1 \u226550% in a Multicenter Real-Life Cohort: The PEMBREIZH Study","volume":"9","author":"Amrane","year":"2020","journal-title":"Cancer Med"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1080\/2162402x.2021.1909296","article-title":"Integrative Evaluation of Primary and Metastatic Lesion Spectrum to Guide Anti-PD-L1 Therapy of Non-Small Cell Lung Cancer: Results From Two Randomized Studies","volume":"10","author":"Ma","year":"2021","journal-title":"Oncoimmunology"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12123707","article-title":"Outcome of Patients With NSCLC and Brain Metastases Treated With Immune Checkpoint Inhibitors in a \u2018Real-Life\u2019 Setting","volume":"12","author":"Skribek","year":"2020","journal-title":"Cancers"},{"key":"B86","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1007\/s00262-019-02462-1","article-title":"Comparable Outcomes of Nivolumab in Patients With Advanced NSCLC Presenting With or Without Brain Metastases: A Retrospective Cohort Study","volume":"69","author":"Zhang","year":"2020","journal-title":"Cancer Immunol Immunother"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13071562","article-title":"Correlation of Clinical Parameters With Intracranial Outcome in Non-Small Cell Lung Cancer Patients With Brain Metastases Treated With Pd-1\/Pd-L1 Inhibitors as Monotherapy","volume":"13","author":"Rounis","year":"2021","journal-title":"Cancers"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2020.11.009","article-title":"Efficacy of Pembrolizumab in Patients With Brain Metastasis Caused by Previously Untreated Non-Small Cell Lung Cancer With High Tumor PD-L1 Expression","volume":"151","author":"Wakuda","year":"2021","journal-title":"Lung Cancer"},{"key":"B89","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.lungcan.2018.12.025","article-title":"Nivolumab and Brain Metastases in Patients With Advanced non-Squamous non-Small Cell Lung Cancer","volume":"129","author":"Crin\u00f2","year":"2019","journal-title":"Lung Cancer (Amsterdam Netherlands)"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.21873\/anticanres.13590","article-title":"Italian Cohort of the Nivolumab EAP in Squamous NSCLC: Efficacy and Safety in Patients With CNS Metastases","volume":"39","author":"Cortinovis","year":"2019","journal-title":"Anticancer Res"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2017.12.008","article-title":"Intracerebral Efficacy and Tolerance of Nivolumab in Non-Small-Cell Lung Cancer Patients With Brain Metastases","volume":"116","author":"Gauvain","year":"2018","journal-title":"Lung Cancer"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12123668","article-title":"Gamma Knife Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer Patients Treated With Immunotherapy or Targeted Therapy","volume":"12","author":"Cho","year":"2020","journal-title":"Cancers"},{"key":"B93","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3171\/2019.4.Jns19822","article-title":"Stereotactic Radiosurgery With and Without Checkpoint Inhibition for Patients With Metastatic Non-Small Cell Lung Cancer to the Brain: A Matched Cohort Study","volume":"133","author":"Shepard","year":"2019","journal-title":"J Neurosurg"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.3171\/2018.10.Jns181371","article-title":"Local Tumor Response and Survival Outcomes After Combined Stereotactic Radiosurgery and Immunotherapy in Non-Small Cell Lung Cancer With Brain Metastases","volume":"132","author":"Singh","year":"2019","journal-title":"J Neurosurg"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2017.11.041","article-title":"Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma","volume":"100","author":"Chen","year":"2018","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.2147\/ott.S286600","article-title":"PD-1\/PD-L1 Inhibitor Combined With Chemotherapy Can Improve the Survival of Non-Small Cell Lung Cancer Patients With Brain Metastases","volume":"13","author":"Sun","year":"2020","journal-title":"Onco Targets Ther"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.21037\/jtd.2018.06.08","article-title":"A Tertiary Care Cancer Center Experience With Carboplatin and Pemetrexed in Combination With Pembrolizumab in Comparison With Carboplatin and Pemetrexed Alone in Non-Squamous Non-Small Cell Lung Cancer","volume":"10","author":"Afzal","year":"2018","journal-title":"J Thorac Dis"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2021.06.020","article-title":"Outcomes With Pembrolizumab Plus Platinum-Based Chemotherapy for Patients With Non-Small-Cell Lung Cancer and Stable Brain Metastases: Pooled Analysis of KEYNOTE-021, 189, and 407","author":"Powell","year":"2021","journal-title":"J Thorac Oncol: Off Publ Int Assoc Study Lung Cancer"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.829451\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,17]],"date-time":"2022-02-17T00:32:28Z","timestamp":1645057948000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.829451\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,17]]},"references-count":98,"alternative-id":["10.3389\/fimmu.2022.829451"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.829451","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,17]]},"article-number":"829451"}}