{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:35:37Z","timestamp":1788950137684,"version":"build-2803163510"},"reference-count":53,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,12,2]],"date-time":"2020-12-02T00:00:00Z","timestamp":1606867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["NET-2016-02361632"],"award-info":[{"award-number":["NET-2016-02361632"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Development of strong immune evasion has been traditionally associated with the late stages of solid tumor progression, since advanced cancers are more likely to have reached the third phase of the immunoediting process. However, by integrating a variety of approaches, evidence for active immune escape mechanisms has been found even in the pre-invasive lesions that later progress to the main NSCLC histotypes. Pre-invasive lesions of adenocarcinoma (LUAD) and of squamous cell carcinoma (LUSC) can show impaired antigen presentation, loss of heterozygosity at the Human Leukocyte Antigen (HLA) region, neoantigen silencing, activation of immune checkpoints, altered TH1\/TH2 cytokine ratios, and immune contexture evolution. Analysis of large panels of LUAD vs. LUSC, of early stage NSCLC vs. normal lung tissue, of specific molecular subsets of NSCLC, and of distinct regions within the same tumor, indicates that all these processes of immune escape continue to evolve in the invasive stage of NSCLC, are associated with inter- and intra-tumor heterogeneity, and contribute to resistance to therapy by immune checkpoint blockade (ICB). In this review, we will discuss the most recent evidence on immune escape mechanisms developing from the precursor to invasive stage in NSCLC, and the contribution of immune evasion to resistance to ICB in lung cancer.<\/jats:p>","DOI":"10.3390\/cancers12123605","type":"journal-article","created":{"date-parts":[[2020,12,2]],"date-time":"2020-12-02T07:49:54Z","timestamp":1606895394000},"page":"3605","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":160,"title":["Immune Escape Mechanisms in Non Small Cell Lung Cancer"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5096-5538","authenticated-orcid":false,"given":"Andrea","family":"Anichini","sequence":"first","affiliation":[{"name":"Human Tumors Immunobiology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina E.","family":"Perotti","sequence":"additional","affiliation":[{"name":"Human Tumors Immunobiology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7451-1300","authenticated-orcid":false,"given":"Francesco","family":"Sgambelluri","sequence":"additional","affiliation":[{"name":"Human Tumors Immunobiology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Mortarini","sequence":"additional","affiliation":[{"name":"Human Tumors Immunobiology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1126\/science.1203486","article-title":"Cancer immunoediting: Integrating immunity\u2019s roles in cancer suppression and promotion","volume":"331","author":"Schreiber","year":"2011","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1016\/j.cell.2017.10.001","article-title":"Allele-specific HLA loss and immune escape in lung cancer evolution","volume":"171","author":"McGranahan","year":"2017","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/j.cell.2017.04.014","article-title":"Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses","volume":"169","author":"Lavin","year":"2017","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e1356145","DOI":"10.1080\/2162402X.2017.1356145","article-title":"EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer","volume":"6","author":"Dong","year":"2017","journal-title":"Oncoimmunology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1158\/2159-8290.CD-18-0689","article-title":"Suppression of STING associated with LKB1 loss in KRAS-driven lung cancer","volume":"9","author":"Kitajima","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1097\/JTO.0000000000000630","article-title":"The 2015 World Health Organization classification of lung tumors. Impact of genetic, clinical and radiologic advances since the 2004 classification","volume":"10","author":"Travis","year":"2015","journal-title":"J. Thorac. Oncol."},{"key":"ref_7","first-page":"5","article-title":"Adenocarcinoma classification: Patterns and prognosis","volume":"110","author":"Kuhn","year":"2018","journal-title":"Pathologica"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Inamura, K. (2018). Clinicopathological characteristics and mutations driving development of early lung adenocarcinoma: Tumor initiation and progression. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19041259"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2978","DOI":"10.1038\/s41467-019-10877-8","article-title":"Multi-region exome sequencing reveals genomic evolution from preneoplasia to lung adenocarcinoma","volume":"10","author":"Hu","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5022","DOI":"10.1158\/0008-5472.CAN-19-0153","article-title":"The immune contexture associates with the genomic landscape in lung adenomatous premalignancy","volume":"79","author":"Krysan","year":"2019","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1016\/j.jtho.2019.07.031","article-title":"Genomic landscape and immune microenvironment features of preinvasive and early invasive lung adenocarcinoma","volume":"14","author":"Zhang","year":"2019","journal-title":"J. Thorac. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Dejima, H., Hu, X., Chen, R., Zhang, J., Fujimoto, J., Parra, E.R., Haymaker, C., Hubert, S., Duose, D., and Soto, S. (2020). Immune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features. MedRxiv.","DOI":"10.1038\/s41467-021-22890-x"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5472","DOI":"10.1038\/s41467-019-13460-3","article-title":"Genomic and immune profiling of pre-invasive lung adenocarcinoma","volume":"10","author":"Chen","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"18","DOI":"10.3389\/fimmu.2020.00018","article-title":"Advances in anti-tumor treatments targeting the CD47\/SIRP\u03b1 Axis","volume":"11","author":"Zhang","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3425","DOI":"10.1158\/1078-0432.CCR-15-2428","article-title":"Molecular pathways: Targeting B7-H3 774 (CD276) for human cancer immunotherapy","volume":"22","author":"Picarda","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/nrc3239","article-title":"The blockade of immune checkpoints in cancer immunotherapy","volume":"12","author":"Pardoll","year":"2012","journal-title":"Nat. Rev. Cancer."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.lungcan.2019.07.001","article-title":"Premalignant lesions of squamous cell carcinoma of the lung: The molecular make-up and factors affecting their progression","volume":"135","author":"Denisov","year":"2019","journal-title":"Lung Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.5858\/2008-132-1073-PP","article-title":"Pulmonary preneoplasia","volume":"132","author":"Dacic","year":"2008","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/s41591-018-0323-0","article-title":"Deciphering the genomic, epigenomic, and transcriptomic landscapes of pre-invasive lung cancer lesions","volume":"25","author":"Teixeira","year":"2019","journal-title":"Nat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1038\/s41586-019-1330-0","article-title":"Immune evasion before tumour invasion in early lung squamous carcinogenesis","volume":"571","author":"Mascaux","year":"2019","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1158\/2159-8290.CD-19-1366","article-title":"Immune surveillance in clinical regression of pre-invasive squamous cell lung cancer","volume":"10","author":"Pennycuick","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/s41586-019-1032-7","article-title":"Neoantigen-directed immune escape in lung cancer evolution","volume":"567","author":"Rosenthal","year":"2019","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"101386","DOI":"10.1016\/j.isci.2020.101386","article-title":"Earlier-phased cancer immunity cycle strongly influences cancer immunity in operable never-smoker lung adenocarcinoma","volume":"23","author":"Kim","year":"2020","journal-title":"iScience"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1126\/science.aaf1490","article-title":"Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade","volume":"351","author":"McGranahan","year":"2016","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1158\/2159-8290.CD-16-0828","article-title":"Evolution of neoantigen landscape during immune checkpoint blockade in non\u2013small cell lung cancer","volume":"7","author":"Anagnostou","year":"2017","journal-title":"Cancer Discov."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1038\/s41467-019-09834-2","article-title":"Molecular subtyping reveals immune alterations associated with progression of bronchial premalignant lesions","volume":"10","author":"Beane","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.cell.2020.06.013","article-title":"Proteogenomic characterization reveals therapeutic vulnerabilities in lung adenocarcinoma","volume":"182","author":"Gillette","year":"2020","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1007\/s00262-018-2147-7","article-title":"The non-small cell lung cancer immune landscape: Emerging complexity, prognostic relevance and prospective significance in the context of immunotherapy","volume":"67","author":"Anichini","year":"2018","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"eaaf8399","DOI":"10.1126\/science.aaf8399","article-title":"Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy","volume":"355","author":"Davoli","year":"2017","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.ejca.2019.08.001","article-title":"Genomic scoring to determine clinical benefit of immunotherapy by targeted sequencing","volume":"120","author":"Kim","year":"2019","journal-title":"Eur. J. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1158\/2159-8290.CD-14-1236","article-title":"Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities","volume":"5","author":"Skoulidis","year":"2015","journal-title":"Cancer Discov."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1158\/0008-5472.CAN-15-1439","article-title":"STK11\/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment","volume":"76","author":"Koyama","year":"2016","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1097\/JTO.0000000000000500","article-title":"Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-driven NSCLC","volume":"10","author":"Chen","year":"2015","journal-title":"J. Thorac. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e1094598","DOI":"10.1080\/2162402X.2015.1094598","article-title":"Upregulation of PD-L1 by EML4-ALK fusion protein mediates the immune escape in ALK positive NSCLC: Implication for optional anti-PD-1\/PD-L1 immune therapy for ALK-TKIs sensitive and resistant NSCLC patients","volume":"5","author":"Hong","year":"2016","journal-title":"Oncoimmunology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1038\/s43018-020-0066-y","article-title":"The T cell differentiation landscape is shaped by tumour mutations in lung cancer","volume":"1","author":"Ghorani","year":"2020","journal-title":"Nat. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Cancer Genome Atlas Research Network (2012). Comprehensive genomic characterization of squamous cell lung cancers. Nature, 489, 519\u2013525.","DOI":"10.1038\/nature11404"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Cancer Genome Atlas Research Network (2014). Comprehensive molecular profiling of lung adenocarcinoma. Nature, 511, 543\u2013550.","DOI":"10.1038\/nature13385"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.jtho.2017.03.010","article-title":"Lung adenocarcinoma and squamous cell carcinoma gene expression subtypes demonstrate significant differences in tumor immune landscape","volume":"12","author":"Faruki","year":"2017","journal-title":"J. Thorac. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e89014","DOI":"10.1172\/jci.insight.89014","article-title":"Multiparametric profiling of non-small-cell lung cancers reveals distinct immunophenotypes","volume":"1","author":"Lizotte","year":"2016","journal-title":"JCI Insight"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"14381","DOI":"10.1038\/ncomms14381","article-title":"Neutrophils dominate the immune cell composition in non-small cell lung cancer","volume":"8","author":"Kargl","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/j.immuni.2018.09.020","article-title":"The lineage-defining transcription factors SOX2 and NKX2-1 determine lung cancer cell fate and shape the tumor immune microenvironment","volume":"49","author":"Mollaoglu","year":"2018","journal-title":"Immunity"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.jtho.2020.01.009","article-title":"STING pathway expression identifies NSCLC with an immune-responsive phenotype","volume":"15","author":"Sen","year":"2020","journal-title":"J. Thorac. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1158\/2159-8290.CD-18-0099","article-title":"STK11\/LKB1 mutations and PD-1 Inhibitor Resistance in KRAS \u2013mutant lung adenocarcinoma","volume":"8","author":"Skoulidis","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Cho, B.C., Lopes, G., Kowalski, D.M., Kasahara, K., Wu, Y., Castro, G., Turna, H.Z., Cristescu, R., Aurora-Garg, D., and Loboda, A. (2020, January 22\u201324). Relationship between STK11 and KEAP1 mutational status and efficacy in KEYNOTE-042: Pembrolizumab monotherapy versus platinum-based chemotherapy as first-line therapy for PD-L1-positive advanced NSCLC. Proceedings of the Annual Meeting of the American Association for Cancer Research 2020, Philadelphia, PA, USA.","DOI":"10.1158\/1538-7445.AM2020-CT084"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e000706","DOI":"10.1136\/esmoopen-2020-000706","article-title":"STK11 and KEAP1 mutations as prognostic biomarkers in an observational real-world lung adenocarcinoma cohort","volume":"5","author":"Doshi","year":"2020","journal-title":"ESMO Open"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1200\/PO.20.00174","article-title":"Two patients with advanced-stage lung adenocarcinoma with radiologic complete response to nivolumab treatment harboring an STK11\/LKB1 mutation","volume":"4","author":"Nadal","year":"2020","journal-title":"JCO Precis. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1158\/2159-8290.CD-19-1409","article-title":"Overcoming genetically based resistance mechanisms to PD-1 blockade","volume":"10","author":"Torrejon","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1158\/2159-8290.CD-19-1510","article-title":"Bempegaldesleukin (NKTR-214) plus nivolumab in patients with advanced solid tumors: Phase I dose-escalation study of safety, efficacy, and immune activation (PIVOT-02)","volume":"10","author":"Diab","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.ccell.2019.08.008","article-title":"An evolutionarily conserved function of polycomb silences the MHC class I antigen presentation pathway and enables immune evasion in cancer","volume":"36","author":"Burr","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1016\/j.cell.2017.10.022","article-title":"Epigenetic therapy ties MYC depletion to reversing immune evasion and treating lung cancer","volume":"171","author":"Topper","year":"2017","journal-title":"Cell"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Perrier, A., Didelot, A., Laurent-Puig, P., Blons, H., and Garinet, S. (2020). Epigenetic mechanisms of resistance to immune checkpoint inhibitors. Biomolecules, 10.","DOI":"10.3390\/biom10071061"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2288","DOI":"10.1056\/NEJMoa1716948","article-title":"Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC","volume":"378","author":"Socinski","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2040","DOI":"10.1056\/NEJMoa1810865","article-title":"Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer","volume":"379","author":"Luft","year":"2018","journal-title":"N. Engl. J. Med."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/12\/3605\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:40:38Z","timestamp":1760179238000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/12\/3605"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,2]]},"references-count":53,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["cancers12123605"],"URL":"https:\/\/doi.org\/10.3390\/cancers12123605","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,2]]}}}