{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T05:23:07Z","timestamp":1777353787197,"version":"3.51.4"},"reference-count":18,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,24]],"date-time":"2021-12-24T00:00:00Z","timestamp":1640304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>High PD-L1 expression in non-small cell lung cancer (NSCLC) is evident to predict elevated immunotherapy efficacy, to which NSCLC with onco-driver gene mutations is probed with poor responsiveness. Thus, it is of great interest to investigate how effective immune monotherapy is in the presence of concurrent high PD-L1 expression and driving gene mutation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients and methods<\/jats:title><jats:p>We present a case of squamous lung cancer with high PD-L1 expression and HER2 exon 20 insertion (20Ins) who presented hyperprogressive disease (HPD) after being treated with PD-1 inhibitor.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A 71-year-old female was diagnosed with advanced squamous lung cancer with 98% tumor proportion score of PD-1 and 20ins. She benefited from first-line docetaxel cisplatin followed by 2 months second-line afatinib. Third-line pembrolizumab monotherapy was then given. Unfortunately, she rapidly progressed with dramatically enlarged primary site as well as mediastinal lymph nodes and pleural effusion only 2 weeks later, presenting severe dyspnea and dysphagia. Re-biopsy was conducted, and we found that compared with the baseline, CD8+ T cells were largely recruited only in tumor stroma but not in tumor parenchyma. Tumor-associated macrophages were notably increased in both tumor stroma and parenchyma. Concomitantly, CD56dim NK cells in tumor parenchyma were decreased.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Application of immune monotherapy in patients with positive driver genes demands extreme caution, even harboring high PD-L1 expression. Abnormality of tumor microenvironment might be critically involved in immune checkpoint inhibitor-induced HPD. Further study in greater depth is required.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2021.760703","type":"journal-article","created":{"date-parts":[[2021,12,24]],"date-time":"2021-12-24T06:53:00Z","timestamp":1640328780000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Case Report: Tumor Microenvironment Characteristics in a Patient With HER2 Mutant Lung Squamous Cell Carcinoma Harboring High PD-L1 Expression Who Presented Hyperprogressive Disease"],"prefix":"10.3389","volume":"11","author":[{"given":"Lixia","family":"Xia","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yinghui","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fen","family":"Lan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junrong","family":"Yan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinfan","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Xia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1200\/PO.19.00333","article-title":"Targeting HER2 Alterations in Non\u2013Small-Cell Lung Cancer: A Comprehensive Review","volume":"3","author":"Zhao","year":"2020","journal-title":"JCO Precis Oncol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1001\/jamaoncol.2018.7098","article-title":"Assessment of Blood Tumor Mutational Burden as a Potential Biomarker for Immunotherapy in Patients With Non-Small Cell Lung Cancer With Use of a Next-Generation Sequencing Cancer Gene Panel","volume":"5","author":"Wang","year":"2019","journal-title":"JAMA Oncol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"3634","DOI":"10.21037\/tcr.2020.04.09","article-title":"The Efficacy of Afatinib in Patients With HER2 Mutant non-Small Cell Lung Cancer: A Meta-Analysis","volume":"9","author":"Zhou","year":"2020","journal-title":"Trans Cancer Res"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.Cd-18-0099","article-title":"STK11\/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma","volume":"8","author":"Skoulidis","year":"2018","journal-title":"Cancer Discovery"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(18)30144-x","article-title":"Durvalumab as Third-Line or Later Treatment for Advanced non-Small-Cell Lung Cancer (ATLANTIC): An Open-Label, Single-Arm, Phase 2 Study","volume":"19","author":"Garassino","year":"2018","journal-title":"Lancet Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(21)02098-5","article-title":"Adjuvant Atezolizumab After Adjuvant Chemotherapy in Resected Stage IB-IIIA non-Small-Cell Lung Cancer (IMpower010): A Randomised, Multicentre, Open-Label, Phase 3 Trial","volume":"398","author":"Felip","year":"2021","journal-title":"Lancet"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2020.12.015","article-title":"Four-Year Survival With Durvalumab After Chemoradiotherapy in Stage III NSCLC-An Update From the PACIFIC Trial","volume":"16","author":"Faivre-Finn","year":"2021","journal-title":"J Thorac Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz167","article-title":"Immune Checkpoint Inhibitors for Patients With Advanced Lung Cancer and Oncogenic Driver Alterations: Results From the IMMUNOTARGET Registry","volume":"30","author":"Mazieres","year":"2019","journal-title":"Ann Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.cllc.2020.12.015","article-title":"Subtypes of EGFR- and HER2-Mutant Metastatic NSCLC Influence Response to Immune Checkpoint Inhibitors","volume":"22","author":"Lau","year":"2021","journal-title":"Clin Lung Cancer"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-16-3133","article-title":"Hyperprogressors After Immunotherapy: Analysis of Genomic Alterations Associated With Accelerated Growth Rate","volume":"23","author":"Kato","year":"2017","journal-title":"Clin Cancer Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2019.05.033","article-title":"Comprehensive Clinical and Genetic Characterization of Hyperprogression Based on Volumetry in Advanced Non-Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitor","volume":"14","author":"Kim","year":"2019","journal-title":"J Thorac Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10501","article-title":"Adaptive Resistance to Therapeutic PD-1 Blockade is Associated With Upregulation of Alternative Immune Checkpoints","volume":"7","author":"Koyama","year":"2016","journal-title":"Nat Commun"},{"key":"B13","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":"B14","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2005.01.4910","article-title":"Macrophage and Mast-Cell Invasion of Tumor Cell Islets Confers a Marked Survival Advantage in non-Small-Cell Lung Cancer","volume":"23","author":"Welsh","year":"2005","journal-title":"J Clin Oncol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1080\/2162402x.2019.1708065","article-title":"Expression of TIM3\/VISTA Checkpoints and the CD68 Macrophage-Associated Marker Correlates With Anti-PD1\/PDL1 Resistance: Implications of Immunogram Heterogeneity","volume":"9","author":"Kato","year":"2020","journal-title":"Oncoimmunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-18-1390","article-title":"Antibody-Fc\/FcR Interaction on Macrophages as a Mechanism for Hyperprogressive Disease in Non-Small Cell Lung Cancer Subsequent to PD-1\/PD-L1 Blockade","volume":"25","author":"Lo Russo","year":"2019","journal-title":"Clin Cancer Res"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/nature21349","article-title":"Elements of Cancer Immunity and the Cancer-Immune Set Point","volume":"541","author":"Chen","year":"2017","journal-title":"Nat"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01398-3","article-title":"An Ex Vivo Tumor Fragment Platform to Dissect Response to PD-1 Blockade in Cancer","volume":"27","author":"Voabil","year":"2021","journal-title":"Nat Med"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.760703\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,24]],"date-time":"2021-12-24T06:53:05Z","timestamp":1640328785000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.760703\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,24]]},"references-count":18,"alternative-id":["10.3389\/fonc.2021.760703"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2021.760703","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,24]]},"article-number":"760703"}}