Evaluating the significance of density, localization, and PD-1/PD-L1 immunopositivity of mononuclear cells in the clinical course of lung adenocarcinoma patients with brain metastasis

Téglási, Vanda; Reiniger, Lilla; Fábián, Katalin; Pipek, Orsolya; Csala, Irén; Bagó, Attila G.; Várallyai, Péter; Vízkeleti, Laura; Rojkó, Lívia; Tı́már, József; Döme, Balázs; Szállási, Zoltán; Swanton, Charles; Moldvay, Judit

doi:10.1093/neuonc/now309

Cited by 37 publications

(30 citation statements)

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“…The brain TME was found to have lost PD-1 + TILs despite their presence in primary lung cancer specimens, which is a novel finding of this study. In accordance with others [31–33], adenocarcinoma patients displayed a more distinctive pattern of a low infiltration of both CD3 + and CD8 + TILs, suggesting that a significant number of patients lack any significant local immune response in association with their BM. Although PD-L1 expression of tumor cells showed no significant differences in this study, others have reported that BM lost PD-L1 expression that was normally present in primary lung cancer specimens [22, 34].…”

Section: Discussionsupporting

confidence: 91%

Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients: therapeutic implications for immune checkpoint inhibitors

et al. 2019

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BackgroundWe aimed to compare intra- and extracranial responses to immune checkpoint inhibitors (ICIs) in lung cancer with brain metastases (BM), and to explore tumor microenvironments of the brain and lungs focusing on the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway.MethodsTwo cohorts of lung cancer patients with BM were analyzed. Cohort 1 included 18 patients treated with nivolumab or pembrolizumab, and intra- and extracranial responses were assessed. Cohort 2 comprised 20 patients who underwent both primary lung surgery and brain metastasectomy. Specimens from cohort 2 were subjected to immunohistochemical analysis for the following markers: CD3, CD4, CD8, FOXP3, and PD-1 on tumor infiltrating lymphocytes (TIL) and PD-L1 on tumor cells.ResultsSeven patients (38.9%) in cohort 1 showed progressive disease in both primary and intracranial lesions. Although the other 11 patients exhibited a partial response or stable disease in the primary lesion, eight showed a progression in BM. Interestingly, PD-1+ TILs were significantly decreased in BM (P = 0.034). For fifteen patients with adenocarcinoma, more distinctive patterns were observed in CD3+ (P = 0.078), CD8+ (P = 0.055), FOXP3+ (P = 0.016), and PD-1+ (P = 0.016) TILs.ConclusionsThere may be discordant responses to an ICI of lung cancer between primary lung lesion and BM based on discrepancies in the tumor microenvironment. The diminished infiltration of PD-1+ TILs in tumor tissue within the brain may be one of the major factors that hinder the response to anti–PD-1 antibody in BM.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5214-8) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 91%

Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients: therapeutic implications for immune checkpoint inhibitors

et al. 2019

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“…High PD-L1 expression has been associated with longer OS in pMMR mCRC in some studies, but not all [31]. In addition, in lung cancer with BM, PD-L1 expression has been associated with worse OS [32]. Our study highlighted two other prognostic markers, single BM and the absence of lung metastases that had already been reported for patients with BM whatever the primary tumor.…”

Section: Discussionsupporting

confidence: 68%

Pathological and Molecular Characteristics of Colorectal Cancer with Brain Metastases

Roussille

Tachon

Villalva

et al. 2018

Cancers

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Background: Colorectal cancers (CRC) with brain metastases (BM) are scarcely described. The main objective of this study was to determine the molecular profile of CRC with BM. Methods: We included 82 CRC patients with BM. KRAS, NRAS, BRAF and mismatch repair (MMR) status were investigated on primary tumors (n = 82) and BM (n = 38). ALK, ROS1, cMET, HER-2, PD-1, PD-L1, CD3 and CD8 status were evaluated by immunohistochemistry, and when recommended, by fluorescence in situ hybridization. Results: In primary tumors, KRAS, NRAS and BRAF mutations were observed in 56%, 6%, and 6% of cases, respectively. No ROS1, ALK and cMET rearrangement was detected. Only one tumor presented HER-2 amplification. Molecular profiles were mostly concordant between BM and paired primary tumors, except for 9% of discordances for RAS mutation. CD3, CD8, PD-1 and PD-L1 expressions presented some discordance between primary tumors and BM. In multivariate analysis, multiple BM, lung metastases and PD-L1+ tumor were predictive of poor overall survival. Conclusions: CRCs with BM are associated with high frequency of RAS mutations and significant discordance for RAS mutational status between BM and paired primary tumors. Multiple BM, lung metastases and PD-L1+ have been identified as prognostic factors and can guide therapeutic decisions for CRC patients with BM.

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“…Lung adenocarcinoma (LAD), the most common subtype of non-small-cell lung cancer (NSCLC) which accounts for the majority of all primary lung cancer cases diagnosed, has a low 5-year survival rate [2,3]. In the past decades, we have made great improvements in the treatment of NSCLC, such as anti-PD-1/PD-L1 therapy [4,5], targetted therapies [6,7], which are also suitable for LAD treatment [8,9]. Meanwhile, the therapeutic strategies for treating LAD also improved [10–12].…”

Section: Introductionmentioning

confidence: 99%

LncRNA TP73-AS1 promoted the progression of lung adenocarcinoma via PI3K/AKT pathway

et al. 2019

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Lung adenocarcinoma (LAD) is one of the most common malignancies that threats human health worldwide. Long non-coding RNAs (lncRNAs) have been reported to play significant roles in tumorigenesis and might be novel biomarkers and targets for diagnosis and treatment of cancers. TP73-AS1 is a newly discovered lncRNA involved in the tumorigenesis and development of several cancers. However, its role in LAD has not been investigated yet. In the present study, we first found that TP73-AS1 expression was markedly increased in LAD tissues and cell lines and its overexpression was strongly associated with poor clinical outcomes. Then the loss/gain-of-function assays elucidated that TP73-AS1 contributed to cell proliferation, migration, and invasion in vitro, and the in vivo experiments illustrated that its knockdown inhibited tumor growth and metastasis. What was more, we discovered that phosphoinositide 3-kinase and AKT (PI3K/AKT) pathway was activated both in LAD tissues and cell lines but inactivated under TP73-AS1 silence. Moreover, the activation of this pathway could rescue the inhibitory effects of TP73-AS1 suppression on LAD cellular processes partially. These data suggested that TP73-AS1 served as an oncogene in LAD partially through activating PI3K/AKT pathway and it could be a potential target for diagnosis and treatment of LAD.

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Evaluating the significance of density, localization, and PD-1/PD-L1 immunopositivity of mononuclear cells in the clinical course of lung adenocarcinoma patients with brain metastasis

Cited by 37 publications

References 51 publications

Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients: therapeutic implications for immune checkpoint inhibitors

Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients: therapeutic implications for immune checkpoint inhibitors

Pathological and Molecular Characteristics of Colorectal Cancer with Brain Metastases

LncRNA TP73-AS1 promoted the progression of lung adenocarcinoma via PI3K/AKT pathway

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