The spatial transcriptomic landscape of non-small cell lung cancer brain metastasis

Zhang, Qi; Abdo, Rober; Iosef, Cristiana; Kaneko, Tomonori; Cecchini, Matthew J.; Han, V. K. M.; Li, Shawn Shun‐Cheng

doi:10.1038/s41467-022-33365-y

Cited by 89 publications

(53 citation statements)

References 77 publications

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“…Homozygous deletions in HLA-B have previously been reported to confer acquired resistance to immune checkpoint inhibitors (ICIs) in LUAD 17 and other work has suggested HLA-B downregulation as a means by which metastatic clones escape T-lymphocyte and NK cell-mediated cytotoxicity 18 . In the context of recent work showing that the brain TME is characterized by reduced antigen presentation and B/T-cell function and increased M2-type macrophage activity 19 , HLA-B alterations in LUAD cells may be permissive for cancer cell growth in the brain TME.…”

Section: Discussionmentioning

confidence: 96%

Genomic analysis and clinical correlations of non-small cell lung cancer (NSCLC) brain metastasis (BM).

Skakodub

Tringale

Walch

et al. 2022

JCO

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2008 Background: Approximately 30% of patients with NSCLC present with BM, and up to 50% of patients ultimately develop BM. While modern NSCLC-directed agents yield excellent systemic response, most patients require focal treatment. Prior reports of BM genomics have been limited by low numbers, missing clinical data, and lack of matched specimens. Here, we report the largest cohort to date of molecularly profiled NSCLC BM samples with clinical correlates. Methods: Clinical data and outcomes for 244 patients with NSCLC and resected BM were identified, and BM samples were assessed with one of four versions (341, 410, 468, 505) of MSK-IMPACT, a custom FDA-approved next generation sequencing-based tumor sequencing assay. 51 (20.9%) patients had matched primary site tissue, and 44 (18%) patients had matched tissue from another metastatic site or CSF. Genomic alterations were filtered for driver variants using OncoKB. Results: Median age was 66 years (range 31-91), and median follow-up was 2.3 years (IQR 1.3-4.3). Adenocarcinoma was the most common histology (183, 78%). Half presented with a single BM, and 121 (51%) patients were treatment naive. Most (197, 83%) received adjuvant stereotactic radiosurgery (SRS) to the resection site and 28% received SRS to additional BM. After resection, 130 (55.1%) had CNS progression, often regional (54, 42%). SRS to new BMs (32%) was the most common salvage treatment. Median overall survival from BM diagnosis was 2.5 years (95%CI 2.1-3.2). Median CNS-progression-free survival was 1.2 years (95%CI 0.9-1.4). The most frequently altered genes in BM samples were TP53 (72%), CDKN2A (34%), KRAS (31%), KEAP1 (26%), and EGFR (21%). CDKN2A was more frequently altered in BM samples when compared to NSCLC primary samples (34% vs 14%, p = 0.003, q = 0.034). With regard to overrepresented gene sets, cell cycle pathway alterations were enriched in BM (56% vs 31%, p = 0.002, q = 0.022). BM samples had a significantly higher fraction of genome altered relative to the primary samples (p < 0.0001, q < 0.0001). After grouping patients based on type of CNS progression, we found that EGFR alterations were enriched in patients with leptomeningeal failures when compared to both patients without progression (42% vs 18%, p = 0.03, q = 0.93) and to patients with either local or regional progression (42% vs 19%, p = 0.03, q = 0.9). Conclusions: In the largest-ever assembled cohort of genomically-profiled NSCLC BM, we found significant enrichment for CDKN2A and cell cycle pathway alterations in BM compared to extracranial disease, as well as a higher fraction of genome altered, in BMs compared to matched primary tumor controls. We also observed EGFR alteration enrichment in patients who develop LMD, suggesting specific biologic underpinnings driving patterns of CNS failure. Further investigation into the role of systemic therapy and time course will elucidate potential mechanisms for CNS failure in patients with NSCLC.

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Section: Discussionmentioning

confidence: 96%

Genomic analysis and clinical correlations of non-small cell lung cancer (NSCLC) brain metastasis (BM).

Skakodub

Tringale

Walch

et al. 2022

JCO

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“…Kudo et al showed increased infiltration of M2 macrophages in brain metastasis from paired NSCLC samples by comparative immune gene profiling analysis [ 21 ]. In a recent study on human NSCLC, Zhang et al showed increased expression of CD163 M2 macrophages in the tumor brain microenvironment and linked this finding with a significant promotion of neo-angiogenesis [ 33 ]. Berghoff et al found differences in the infiltration of microglia and M2 macrophages between brain metastasis from NSCLC and melanoma [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Tumor lineage-specific immune response in brain metastatic disease: opportunities for targeted immunotherapy regimen?

Najjary

Kros

Koning

et al. 2023

acta neuropathol commun

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Metastases in the brain are the most severe and devastating complication of cancer. The incidence of brain metastasis is increasing. Therefore, the need of finding specific druggable targets for brain metastasis is demanding. The aim of this study was to compare the brain (immune) response to brain metastases of the most common tumor lineages, viz., lung adenocarcinoma and breast cancer. Targeted gene expression profiles of 11 brain metastasis of lung adenocarcinoma (BM-LUAD) were compared to 11 brain metastasis of breast cancer (BCBM) using NanoString nCounter PanCancer IO 360™ Panel. The most promising results were validated spatially using the novel GeoMx™ Digital Spatial Profiler (DSP) Technology. Additionally, Immune cell profiles and expression of drug targets were validated by multiplex immunohistochemistry. We found a more active immune response in BM-LUAD as compared to BCBM. In the BM-LUAD, 138 genes were upregulated as compared to BCBM (adj. p ≤ 0.05). Conversely, in BCBM 28 genes were upregulated (adj. p ≤ 0.05). Additionally, genes related to CD45 + cells, T cells, and cytotoxic T cells showed to be expressed higher in BM-LUAD compared to BCBM (adj. p = 0.01, adj. p = 0.023, adj. p = 0.023, respectively). The spatial quantification of the immune cells using the GeoMx DSP technique revealed the significantly higher quantification of CD14 and CD163 in tumor regions of BM-LUAD as compared to BCBM. Importantly, the immune checkpoint VISTA and IDO1 were identified as highly expressed in the BM-LUAD. Multiplex immunohistochemistry confirmed the finding and showed that VISTA is expressed mainly in BM-LUAD tumor cells, CD3 + cells, and to fewer levels in some microglial cells in BM-LUAD. This is the first report on differences in the brain immune response between metastatic tumors of different lineages. We found a far more extensive infiltration of immune cells in BM-LUAD as compared to BCBM. In addition, we found higher expression of VISTA and IDO1 in BM-LUAD. Taken together, targeted immune therapy should be considered to treat patients with BM-LUAD.

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“…Changes in the functional status of astrocytes, which are the stromal cells of the central nervous system, have varying impacts on the microenvironment of brain metastases. According to studies, reactive astrocytes help create a fibrotic tumor brain microenvironment that is unfavorable to the effects of immunotherapy ( 115 ). Additionally, one of the significant elements influencing the effectiveness of immunotherapy is the quantity and activity of lymphocytes in brain metastases, and efficient T cells contribute to this improvement ( 116 ).…”

Section: Discussion and Prospectsmentioning

confidence: 99%

Microenvironment and the progress of immunotherapy in clinical practice of NSCLC brain metastasis

Xie

2023

Front. Oncol.

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One of the most frequent distant metastases of lung cancer occurs in the brain. The average natural survival duration for patients with lung cancer who have brain metastases is about 1 to 2 months. Knowledge about brain metastases is currently restricted since they are more difficult to acquire than other metastases. This review begins with an analysis of the immune microenvironment of brain metastases; focuses primarily on the functions of microglia, astrocytes, neurons, and tumor-infiltrating lymphocytes in the microenvironment of brain metastases; and offers an atlas of the immune microenvironment of brain metastases involving significant cells. In an effort to give researchers new research ideas, the study also briefly covers how immunotherapy for non-small cell lung cancer with brain metastases is currently faring.

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The spatial transcriptomic landscape of non-small cell lung cancer brain metastasis

Cited by 89 publications

References 77 publications

Genomic analysis and clinical correlations of non-small cell lung cancer (NSCLC) brain metastasis (BM).

Genomic analysis and clinical correlations of non-small cell lung cancer (NSCLC) brain metastasis (BM).

Tumor lineage-specific immune response in brain metastatic disease: opportunities for targeted immunotherapy regimen?

Microenvironment and the progress of immunotherapy in clinical practice of NSCLC brain metastasis

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