Characterisation of the immune microenvironment of primary breast cancer and brain metastasis reveals depleted T-cell response associated to ARG2 expression

Giannoudis, Athina; Varešlija, Damir; Sharma, Vagisha; Zakaria, Rasheed; Platt-Higgins, Angela; Rudland, Philip S.; Jenkinson, Michael D.; Young, Leonie S.; Palmieri, Carlo

doi:10.1016/j.esmoop.2022.100636

Cited by 10 publications

(10 citation statements)

References 54 publications

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“…48 We recently showed that PD-L1 and CTLA4 transcripts were signi cantly higher in TN BCBMs, with CTLA4 expression also high in HER2-positive compared to estrogen receptor-positive BCBMs. 49 Studies of immunotherapy in the context of melanoma and non-squamous cell lung have provided proof of concept that immunotherapy can modulate intracranial disease and result in clinical bene t in intracranial disease. [50][51][52] Given these data, the role of immunotherapy in appropriately biomarker selected breast cancer patients with BCBM should be explored.…”

Section: Discussionmentioning

confidence: 99%

Identification of targetable genomic profiling of breast cancer brain metastases identifies alterations and genomic signatures relevant to immune-checkpoint and PARP inhibitors

Palmieri

Giannoudis

Sokol³

et al. 2023

Preprint

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Understanding the genomic landscape of breast cancer brain metastases (BCBMs) is key to elucidating their cause and developing novel treatments. In this study, comprehensive genomic profiling was performed on 822 BCBMs, 11,988 local breast cancer (BC) biopsies and 15,516 non-central nervous system (N-CNS) metastases (all unpaired samples). Clinically-relevant genomic alterations were significantly enriched in BCBMs compared to local BCs and N-CNS metastases. Homologous recombination deficiency as measured by BRCA1/2alteration prevalence and loss-of-heterozygosity and immune checkpoint inhibitor (ICI) biomarkers [Tumour mutation burden (TMB)-High, Microsatellite instability (MSI)-High, PD-L1/L2)] were significantly more prevalent in BCBM than local BC and N-CNS. High PD-L1 protein expression was observed in ER-negative/HER2-negative BCBMs (48.3% vs 50.0% in local BCs, 21.4% in N-CNS). Collectively, our data highlights that a high proportion of BCBMs are potentially amenable to treatment with targeted therapeutic agents including PARP inhibitors and ICIs.

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Section: Discussionmentioning

confidence: 99%

Identification of targetable genomic profiling of breast cancer brain metastases identifies alterations and genomic signatures relevant to immune-checkpoint and PARP inhibitors

Palmieri

Giannoudis

Sokol³

et al. 2023

Preprint

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“…A study by Noh et al exploring the evolution of the tumor microenvironment in BC BM found that a lower CD8+ T cell count, low CD86+ M1 macrophage count, and high M2/M1 macrophage ratio in the BC BM compared to the primary tumor were related to unfavorable clinical outcomes [ 47 ]. Furthermore, Giannoudis et al have conducted an analysis of 55 samples consisting of 26 paired primary BCs and their BMs, assessing TILs and mRNA expression [ 48 ]. Authors have demonstrated a significant reduction of TILs in BC BMs in comparison to primary BCs, with an 11.5% high-TILs count in primary tumors (>40% stromal TILs) versus only 3.8% in BC BMs [ 48 ].…”

Section: Biological Mechanisms Of Brain Metastasismentioning

confidence: 99%

“…Furthermore, Giannoudis et al have conducted an analysis of 55 samples consisting of 26 paired primary BCs and their BMs, assessing TILs and mRNA expression [ 48 ]. Authors have demonstrated a significant reduction of TILs in BC BMs in comparison to primary BCs, with an 11.5% high-TILs count in primary tumors (>40% stromal TILs) versus only 3.8% in BC BMs [ 48 ]. A total of 112 immune-related gene levels were found to decrease in BC BMs compared to primary BCs, including PD-L1 and cytotoxic T-lymphocyte antigen 4 (CTLA-4) (false discovery rate < 0.01, log2 fold-change > 1.5), which are involved in cytokine–chemokine signaling, immune cells migration, matrix remodeling, and metastasis [ 48 ].…”

Section: Biological Mechanisms Of Brain Metastasismentioning

confidence: 99%

“…Authors have demonstrated a significant reduction of TILs in BC BMs in comparison to primary BCs, with an 11.5% high-TILs count in primary tumors (>40% stromal TILs) versus only 3.8% in BC BMs [ 48 ]. A total of 112 immune-related gene levels were found to decrease in BC BMs compared to primary BCs, including PD-L1 and cytotoxic T-lymphocyte antigen 4 (CTLA-4) (false discovery rate < 0.01, log2 fold-change > 1.5), which are involved in cytokine–chemokine signaling, immune cells migration, matrix remodeling, and metastasis [ 48 ]. CTLA-4 is one of the fundamental immunosuppressive cytokines, mainly activated on T-cells, which suppresses the immune response, and potentially prevents cancer cells from being attacked by the immune system.…”

Section: Biological Mechanisms Of Brain Metastasismentioning

confidence: 99%

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Breast Cancer with Brain Metastasis: Molecular Insights and Clinical Management

Ivanova,

Porta,

Giugliano

et al. 2023

Genes

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Breast cancer is the most frequently diagnosed malignancy worldwide and the leading cause of cancer-related death among women. Brain metastases are a primary contributor to mortality, as they often go undetected until late stages due to their dormant nature. Moreover, the clinical management of brain metastases is complicated by the relevant issue of blood-brain barrier penetration. The molecular pathways involved in the formation, progression, and colonization of primary breast tumors and subsequent brain metastases are diverse, posing significant hurdles due to the heterogeneous nature of breast cancer subtypes. Despite advancements in primary breast cancer treatments, the prognosis for patients with brain metastases remains poor. In this review, we aim to highlight the biological mechanisms of breast cancer brain metastases by evaluating multi-step genetic pathways and to discuss currently available and emerging treatment strategies to propose a prospective overview of the management of this complex disease.

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“…Additionally, astrocytes which express signal transducer and activator of transcription 3 (STAT3) contribute to BrM by regulating innate and specific immunity as well as establish gap junctions with metastases cells to enhance the growth ability and drug resistance of tumor cells ( Chen et al, 2016 ; Sato et al, 2017 ; Priego et al, 2018 ; Kim et al, 2019 ; Song S. G. et al, 2021 ; Song Z. et al, 2021 ). When compared with primary breast cancer, breast cancer BrM tends to have lower infiltration of immune cells (macrophages, microglia, lymphocytes, and monocytes), lower protein and gene expression of immune activation markers (CD27, T cell immunoglobulin and mucin-domain containing-3 (Tim-3), and CD137), and lower expression of immune-related genes (PD-L1 and CTLA-4) ( Schlam et al, 2021 ; Giannoudis et al, 2022 ). In melanoma BrM, oxidative phosphorylation (OXPHOS) gene set in Kyoto Encyclopedia of Genes and Genomes (KEGG) database is enriched compared with primary cancer ( Fischer et al, 2019 ), while melanoma BrM has lower T-cell content and microvessel density ( Weiss et al, 2021 ).…”

Section: The Uniqueness Of Brm Microenvironmentmentioning

confidence: 99%

The progress of microenvironment-targeted therapies in brain metastases

Long

Yi²,

Zeng³

et al. 2023

Front. Mol. Biosci.

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The incidence of brain metastases (BrM) has become a growing concern recently. It is a common and often fatal manifestation in the brain during the end-stage of many extracranial primary tumors. Increasing BrM diagnoses can be attributed to improvements in primary tumor treatments, which have extended patients’ lifetime, and allowed for earlier and more efficient detection of brain lesions. Currently, therapies for BrM encompass systemic chemotherapy, targeted therapy, and immunotherapy. Systemic chemotherapy regimens are controversial due to their associated side effects and limited efficacy. Targeted and immunotherapies have garnered significant attention in the medical field: they target specific molecular sites and modulate specific cellular components. However, multiple difficulties such as drug resistance and low permeability of the blood-brain barrier (BBB) remain significant challenges. Thus, there is an urgent need for novel therapies. Brain microenvironments consist of cellular components including immune cells, neurons, endothelial cells as well as molecular components like metal ions, nutrient molecules. Recent research indicates that malignant tumor cells can manipulate the brain microenvironment to change the anti-tumoral to a pro-tumoral microenvironment, both before, during, and after BrM. This review compares the characteristics of the brain microenvironment in BrM with those in other sites or primary tumors. Furthermore, it evaluates the preclinical and clinical studies of microenvironment-targeted therapies for BrM. These therapies, due to their diversity, are expected to overcome drug resistance or low permeability of the BBB with low side effects and high specificity. This will ultimately lead to improved outcomes for patients with secondary brain tumors.

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Characterisation of the immune microenvironment of primary breast cancer and brain metastasis reveals depleted T-cell response associated to ARG2 expression

Cited by 10 publications

References 54 publications

Identification of targetable genomic profiling of breast cancer brain metastases identifies alterations and genomic signatures relevant to immune-checkpoint and PARP inhibitors

Identification of targetable genomic profiling of breast cancer brain metastases identifies alterations and genomic signatures relevant to immune-checkpoint and PARP inhibitors

Breast Cancer with Brain Metastasis: Molecular Insights and Clinical Management

The progress of microenvironment-targeted therapies in brain metastases

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