{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T17:39:59Z","timestamp":1793209199851,"version":"4.5.0"},"reference-count":63,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2023,3,3]],"date-time":"2023-03-03T00:00:00Z","timestamp":1677801600000},"content-version":"unspecified","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Multidisciplinary Cooperative Diagnosis and Treatment Capacity Building Project for Major Diseases of Chin","award":["z027002"],"award-info":[{"award-number":["z027002"]}]},{"name":"Advanced Lung Cancer Research Fund for targeted therapy in China","award":["CTONG-YC20210303"],"award-info":[{"award-number":["CTONG-YC20210303"]}]},{"name":"Beijing Xisike Clinical Oncology and Research Foundation","award":["Y-HR2019-0185"],"award-info":[{"award-number":["Y-HR2019-0185"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2023,2,20]]},"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Previous studies found that lung adenocarcinomas (LUAD) with EGFR-positive and ALK-positive were less responsive to immunotherapy, which may be associated with a suppressive tumor immune microenvironment (TIME). Given the discordance in the TIME between primary lung cancer and brain metastasis, it is urgent to explore the TIME in patients with EGFR\/ALK-positive LUAD with brain metastases (BMs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The transcriptome feature of formalin-fixed and paraffin-embedded samples of BMs and paired primary LUAD from 70 patients with LUAD BMs was illustrated by RNA-sequencing. Six of them were available for paired sample analysis. Then, after excluding 3 co-occurring patients, we divided 67 BMs patients into 41 EGFR\/ALK-positive and 26 EGFR\/ALK-negative patients. The differences in immune profiling between the two groups were analyzed from three dimensions: TIME, T-cell receptor repertoire, and immunohistochemistry. Finally, the survival data of 55 patients were collected.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Compared with primary LUAD, BMs present an immunosuppressed TIME, manifested as: inhibition of immune-related pathways; low expression of immune checkpoint; decreased infiltration of CD8+T cells and cytotoxic lymphocyte; increased proportion of suppressive M2 macrophages. In different subgroups based on EGFR\/ALK gene variation status, both EGFR-positive and ALK-positive tumors present a relatively immunosuppressive microenvironment, but the heterogeneity of tumor microenvironment may undergo different mechanisms. EGFR-positive BMs showed decreased CD8+T cells and increased regulatory T cells (Treg) cells, while ALK-positive BMs showed decreased CD8+T cells and increased M2 macrophages. Moreover, in the TCGA-LUAD cohort, EGFR-positive tumors showed reduced CD8+T\u2009cell infiltrations (p&lt;0.001) and borderline significantly higher Tregs than EGFR\/ALK-negative (p=0.072). In parallel, ALK-positive tumors had higher median M2 macrophages infiltrations than EGFR\/ALK-negative (p=0.175), although there was no statistical significance. Collectively, there was a similar immunosuppressive milieu between EGFR\/ALK-positive primary LUAD and BMs. Moreover, survival analysis uncovered higher CD8A expression, cytotoxic lymphocyte infiltration, and immune scores were significantly associated with better prognosis in both EGFR\/ALK-positive and EGFR\/ALK-negative groups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study found that LUAD-derived BMs exhibited an immunosuppressive TIME and revealed that EGFR-positive and ALK-positive BMs exhibited different immunosuppressive characteristics. Meanwhile, EGFR-negative BMs showed a potential benefit to immunotherapy. These findings boost molecular and clinical understanding of LUAD BMs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2022-006243","type":"journal-article","created":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T06:12:05Z","timestamp":1678947125000},"page":"e006243","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":36,"title":["Heterogeneity of tumor immune microenvironment of EGFR\/ALK-positive tumors versus EGFR\/ALK-negative tumors in resected brain metastases from lung adenocarcinoma"],"prefix":"10.1136","volume":"11","author":[{"given":"Gang","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Xiangya Hospital Central South University, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lifeng","family":"Li","sequence":"additional","affiliation":[{"name":"Geneplus-Beijing, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guilong","family":"Tanzhu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Xiangya Hospital Central South University, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Xiangya Hospital Central South University, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Gao","sequence":"additional","affiliation":[{"name":"Institute of Microbiology, Chinese Academy of Sciences, State Key Laboratory of Microbial Resources, Beijing, China"},{"name":"GenePlus-Shenzhen Clinical Laboratory, Shenzhen, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Xiangya Hospital Central South University, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desheng","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Pathology, Xiangya Hospital Central South University, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Xiangya Hospital Central South University, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefeng","family":"Xia","sequence":"additional","affiliation":[{"name":"Geneplus-Beijing, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4483-0615","authenticated-orcid":false,"given":"Rongrong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Xiangya Hospital Central South University, Changsha, Hunan, China"},{"name":"Xiangya Lung Cancer Center, Xiangya Hospital Central South University, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2023,3,3]]},"reference":[{"key":"2025100309215918000_11.3.e006243.1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.10541"},{"key":"2025100309215918000_11.3.e006243.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cllc.2014.04.008"},{"key":"2025100309215918000_11.3.e006243.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2015.01.020"},{"key":"2025100309215918000_11.3.e006243.4","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1978.00500350058012"},{"key":"2025100309215918000_11.3.e006243.5","doi-asserted-by":"crossref","unstructured":"Achrol AS , Rennert RC , Anders C , et al . 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