{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T06:24:55Z","timestamp":1787639095867,"version":"build-2736575974"},"reference-count":47,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T00:00:00Z","timestamp":1783123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T00:00:00Z","timestamp":1783123200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81970034"],"award-info":[{"award-number":["81970034"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Ther Adv Med Oncol"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Immunotherapy has demonstrated limited efficacy in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), often due to an immunosuppressive tumor microenvironment (TME). The clinical significance of the CD39-adenosine pathway in this refractory setting remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective:<\/jats:title>\n                    <jats:p>To explore the role of the CD39-adenosine pathway, especially CD39, in EGFR-mutant (EGFR-Mu) NSCLC patients who received immunotherapy as a second or later-line treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design:<\/jats:title>\n                    <jats:p>\n                      In this retrospective study, clinical characteristics, treatment regimens, and efficacy endpoints (progression-free survival (PFS) and objective response rate (ORR)) were collected. We analyzed the correlation between CD39 expression, CD39\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell infiltration, and clinical outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      We retrospectively evaluated EGFR-Mu NSCLC patients receiving later-line immune checkpoint inhibitors (ICIs) at Jinling Hospital, alongside The Cancer Genome Altas (TCGA) cohort data. TME phenotyping (CD39, CD73, ADORA1, and CD39\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      \/PD-1\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell infiltration) was performed using immunohistochemistry and immunofluorescence. Patients were divided into a response group and a non-response group according to the Tumor Efficacy Assessment Criteria (RECIST 1.1). Univariate and multivariate Cox regression analyses were used to explore the factors influencing the survival of EGFR-Mu patients who received ICIs in the second line or later lines.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Database and clinical samples analyses revealed that expression of CD39 and CD73 was significantly increased in EGFR-Mu NSCLC samples compared to EGFR wild-type (EGFR-WT). However, Immunofluorescence (IF) results showed that the infiltration rate of CD39\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells was significantly lower in EGFR-Mu patients than in EGFR-WT patients. Notably, low overall CD39 expression and high CD39\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell infiltration within the TME were correlated with favorable immunotherapy responses. Among the 19 EGFR-Mu patients receiving ICIs, the overall ORR was 10.5%, and the median PFS for EGFR-Mu patients was 4.53\u2009months. Multivariate Cox regression analysis found brain metastasis as an independent risk factor, while the infiltration of CD39\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells and PD-1\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells independently correlated with prolonged PFS.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>\n                      Our exploratory findings suggest that CD39\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell infiltration may serve as a putative biomarker associated with immunotherapy response in EGFR-mutant NSCLC. Evaluating the CD39-adenosine pathway within the TME could inform future personalized treatment strategies, warranting further validation in larger, prospective cohorts.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/17588359261458240","type":"journal-article","created":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T12:11:16Z","timestamp":1783167076000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["CD39+CD8+ T cell infiltration is associated with clinical outcomes of subsequent immunotherapy in advanced EGFR-mutant non-small cell lung cancer"],"prefix":"10.1177","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0564-6110","authenticated-orcid":false,"given":"Wanjun","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2551-8188","authenticated-orcid":false,"given":"Qiuxia","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5724-9892","authenticated-orcid":false,"given":"Zimu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4643-232X","authenticated-orcid":false,"given":"Qinpei","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6030-7782","authenticated-orcid":false,"given":"Xueying","family":"Zuo","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0214-8975","authenticated-orcid":false,"given":"Xin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6799-7875","authenticated-orcid":false,"given":"Jiawen","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2391-5820","authenticated-orcid":false,"given":"Yong","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7464-3434","authenticated-orcid":false,"given":"Fang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0987-6770","authenticated-orcid":false,"given":"Tangfeng","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,7,4]]},"reference":[{"key":"e_1_3_4_2_2","first-page":"10","article-title":"Cancer statistics, 2025;","volume":"75","author":"Siegel RL","year":"2025","unstructured":"Siegel RL, Kratzer TB, Giaquinto AN, et al. Cancer statistics, 2025;. CA Cancer J Clin 2025 75: 10\u201345.","journal-title":"CA Cancer J Clin"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-011110-130206"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40364-024-00566-0"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.01626"},{"key":"e_1_3_4_6_2","first-page":"387","article-title":"Personalized care for patients with EGFR-mutant nonsmall cell lung cancer: navigating early to advanced disease management","volume":"75","author":"Borgeaud M","year":"2025","unstructured":"Borgeaud M, Olivier T, Bar J, et al. Personalized care for patients with EGFR-mutant nonsmall cell lung cancer: navigating early to advanced disease management. CA Cancer J Clin 2025; 75: 387\u2013409.","journal-title":"CA Cancer J Clin"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-021-00195-8"},{"key":"e_1_3_4_8_2","article-title":"Navigating the landscape of EGFR TKI resistance in EGFR-mutant NSCLC\u2014mechanisms and evolving treatment approaches","author":"Zhao J","year":"2025","unstructured":"Zhao J, Xu W, Zhou F, et al. Navigating the landscape of EGFR TKI resistance in EGFR-mutant NSCLC\u2014mechanisms and evolving treatment approaches. Nat Rev Clin Oncol 2025; 23: 63\u201383.","journal-title":"Nat Rev Clin Oncol"},{"key":"e_1_3_4_9_2","article-title":"De-escalation strategies with immune checkpoint blockers in non-small cell lung cancer: do we already have enough evidence?","volume":"43","author":"Jordi R","year":"2025","unstructured":"Jordi R, Martina B, Paolo B, et al. De-escalation strategies with immune checkpoint blockers in non-small cell lung cancer: do we already have enough evidence? J Clin Oncol 2025; 43: 1148\u20131156.","journal-title":"J Clin Oncol"},{"key":"e_1_3_4_10_2","article-title":"Immune checkpoint inhibitors rechallenge in non-small cell lung cancer: current evidence and future directions","volume":"604","author":"Xiaoyu G","year":"2024","unstructured":"Xiaoyu G, Jinshan Y, Xin L, et al. Immune checkpoint inhibitors rechallenge in non-small cell lung cancer: current evidence and future directions. Cancer Lett 2024; 604: 217241.","journal-title":"Cancer Lett"},{"key":"e_1_3_4_11_2","article-title":"Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (Checkmate 017 and Checkmate 057)","volume":"35","author":"Leora H","year":"2017","unstructured":"Leora H, David RS, Everett EV, et al. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (Checkmate 017 and Checkmate 057). J Clin Oncol 2017; 35: 3924\u20133933.","journal-title":"J Clin Oncol"},{"key":"e_1_3_4_12_2","article-title":"Five year survival update from keynote-010: pembrolizumab versus docetaxel for previously treated, programmed death-ligand 1-positive advanced NSCLC","volume":"16","author":"Roy SH","year":"2021","unstructured":"Roy SH, Edward BG, Dong-Wan K, et al. Five year survival update from keynote-010: pembrolizumab versus docetaxel for previously treated, programmed death-ligand 1-positive advanced NSCLC. J Thorac Oncol 2021; 16: 1718\u20131732.","journal-title":"J Thorac Oncol"},{"key":"e_1_3_4_13_2","article-title":"Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (Oak): a phase 3, open-label, multicentre randomised controlled trial","volume":"389","author":"Achim R","year":"2016","unstructured":"Achim R, Fabrice B, Daniel W, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (Oak): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2016; 389: 255\u2013265.","journal-title":"Lancet"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2021.04.003"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2021.01.010"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(19)30084-0"},{"key":"e_1_3_4_17_2","article-title":"Final overall survival and safety update for durvalumab in third- or later-line advanced NSCLC: the phase II Atlantic Study","volume":"147","author":"Marina Chiara G","year":"2020","unstructured":"Marina Chiara G, Byoung-Chul C, Joo-Hang K, et al. Final overall survival and safety update for durvalumab in third- or later-line advanced NSCLC: the phase II Atlantic Study. Lung Cancer 2020; 147: 137\u2013142.","journal-title":"Lung Cancer"},{"key":"e_1_3_4_18_2","article-title":"Integrative transcriptome analysis reveals the molecular events underlying impaired T-cell responses in EGFR-mutant lung cancer","volume":"14","author":"Yu Z","year":"2024","unstructured":"Yu Z, Gu T, Jun L, et al. Integrative transcriptome analysis reveals the molecular events underlying impaired T-cell responses in EGFR-mutant lung cancer. Sci Rep 2024; 14: 18366.","journal-title":"Sci Rep"},{"key":"e_1_3_4_19_2","article-title":"Immunological features of EGFR-mutant non-small cell lung cancer and clinical practice: a narrative review","volume":"4","author":"Yi D","year":"2024","unstructured":"Yi D, Liaqat K, Yi Y. Immunological features of EGFR-mutant non-small cell lung cancer and clinical practice: a narrative review. J Natl Cancer Cent 2024; 4: 289\u2013298.","journal-title":"J Natl Cancer Cent"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2017.86"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-020-0382-2"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12528"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-018-0360-8"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2019.10.007"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00698"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2020.12.010"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0376-4"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6602678"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa407"},{"key":"e_1_3_4_30_2","unstructured":"IBM Corp. IBM SPSS statistics for windows (Version 26.0). IBM Corp.: Armonk NY 2020. https:\/\/www.ibm.com."},{"key":"e_1_3_4_31_2","unstructured":"GraphPad Software. GraphPad Prism (version 9.0). San Diego CA: GraphPad Software; 2020. https:\/\/www.graphpad.com (2020)."},{"key":"e_1_3_4_32_2","unstructured":"R Core Team. R: A Language and Environment for Statistical Computing (Version 4.5.2). R Foundation for Statistical Computing Vienna Austria 2024. https:\/\/www.R-project.org"},{"key":"e_1_3_4_33_2","unstructured":"Wei T Simko V. Corrplot: visualization of a correlation matrix (R Package Version 0.92). CRAN https:\/\/CRAN.R-project.org\/package=corrplot (2021 accessed 21 October 2025)."},{"key":"e_1_3_4_34_2","unstructured":"Wickham H. Ggplot2: elegant graphics for data analysis. Springer-Verlag New York. https:\/\/ggplot2.tidyverse.org (2016 accessed 21 October 2025)."},{"key":"e_1_3_4_35_2","unstructured":"Kassambara A. Ggpubr: \u2018Ggplot2\u2019 Based Publication Ready Plots (R Package Version 0.6.0). CRAN. https:\/\/CRAN.R-project.org\/package=ggpubr (2023 accessed 21 October 2025)."},{"key":"e_1_3_4_36_2","unstructured":"Schloerke B Crowley J Cook D et al. Ggally: extension to \u2018Ggplot2\u2019 (R Package Version 2.2.1). CRAN. https:\/\/CRAN.R-project.org\/package=GGally (2024 accessed 21 October 2025)."},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.02.016"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2020.107753"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0130-2"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-2684"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.10.038"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-020-02563-2"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.202048534"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20240445"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-12-064527"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-22-0260"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2022.12.001"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2021.04.016"}],"updated-by":[{"DOI":"10.1177\/17588359261481357","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000}}],"container-title":["Therapeutic Advances in Medical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/17588359261458240","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/17588359261458240","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/17588359261458240","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T05:31:22Z","timestamp":1787635882000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/17588359261458240"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,4]]},"references-count":47,"alternative-id":["10.1177\/17588359261458240"],"URL":"https:\/\/doi.org\/10.1177\/17588359261458240","relation":{},"ISSN":["1758-8359","1758-8359"],"issn-type":[{"value":"1758-8359","type":"print"},{"value":"1758-8359","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,4]]},"article-number":"17588359261458240"}}