Blood–Brain Barrier, Cell Junctions, and Tumor Microenvironment in Brain Metastases, the Biological Prospects and Dilemma in Therapies

Brain metastasis is the most commonly seen brain malignancy, frequently originating from lung cancer, breast cancer, and melanoma. Brain tumor has its unique cell types, anatomical structures, metabolic constraints, and immune environment, which namely the tumor microenvironment (TME). It has been discovered that the tumor microenvironment can regulate the progression, metastasis of primary tumors, and response to the treatment through the particular cellular and non-cellular components. Brain metastasis tumor cells that penetrate the brain–blood barrier and blood–cerebrospinal fluid barrier to alter the function of cell junctions would lead to different tumor microenvironments. Emerging evidence implies that these tumor microenvironment components would be involved in mechanisms of immune activation, tumor hypoxia, antiangiogenesis, etc. Researchers have applied various therapeutic strategies to inhibit brain metastasis, such as the combination of brain radiotherapy, immune checkpoint inhibitors, and monoclonal antibodies. Unfortunately, they hardly access effective treatment. Meanwhile, most clinical trials of target therapy patients with brain metastasis are always excluded. In this review, we summarized the clinical treatment of brain metastasis in recent years, as well as their influence and mechanisms underlying the differences between the composition of tumor microenvironments in the primary tumor and brain metastasis. We also look forward into the feasibility and superiority of tumor microenvironment-targeted therapies in the future, which may help to improve the strategy of brain metastasis treatment.

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Use of brain radiotherapy as part of first course of treatment for NSCLC with de novo brain metastasis.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9118 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9118-9118

Author(s):

Rafael Arteta-Bulos ◽

Nadeem Bilani ◽

Leah Elson ◽

Elizabeth Blessing Elimimian ◽

Diana Saravia ◽

...

Keyword(s):

Brain Metastasis ◽

De Novo ◽

Local Therapy ◽

Insurance Status ◽

Primary Tumors ◽

Brain Radiotherapy ◽

Facility Type ◽

Brain Radiation ◽

To Receive ◽

N Staging

9118 Background: Loco-regional management of brain metastases from non-small cell lung cancer (NSCLC) are surgery and/or brain radiotherapy, either whole brain (WBRT) or stereotactic (SRS). We used a national registry to evaluate trends in the use of brain radiotherapy as part of the first course of management in patients diagnosed with de novo brain metastasis. Methods: We retrospectively analyzed the National Cancer Database (NCDB) to identify patients with NSCLC and de novo brain metastasis diagnosed from 2004-2016. We described the socio-demographic and clinical characteristics of this population, then used chi-squared testing to evaluate for an association between these variables and the use of brain radiotherapy (either SRS or WBRT). Significant variables (p < 0.05) were included in a multiple logistic regression model. Results: Of n = 41,454 patients with NSCLC and de novo brain metastasis, n = 27,949 (67.4%) received either SRS or WBRT as part of their first course of treatment, while n = 13,505 (32.6%) did not receive primary brain radiation. Of those that did not receive radiation: n = 9,927 (73.5%) were < 70 years old while n = 3,578 (26.5%) were ≥70. N = 11,081 (82.7%) were White, n = 1,550 (11.6%) were Black and n = 768 (5.7%) were Asian. Variables significantly associated with the use of primary brain radiotherapy at the multivariate level were: treatment facility type (p = 0.004), tumor histology (p < 0.001), clinical T-staging (p < 0.001), and clinical N-staging (p < 0.001). Age, sex, race, comorbidity, grade, insurance status, and setting (metro vs. rural vs. urban) were not significantly associated with the use of radiotherapy. Compared to patients treated at community cancer programs (CPs), those treated at comprehensive community CPs (OR 1.152, 95% CI 1.027-1.291, p = 0.015) and academic CPs (OR 1.242, 95% CI 1.104-1.398, p < 0.001) were more likely to receive primary brain radiotherapy. Patients with squamous NSCLC were less likely (OR 0.680, 95% CI 0.619-0.747, p < 0.001) to receive brain radiotherapy compared to those with adenocarcinoma. Finally, patients with advanced T-staging (p < 0.001) and N-staging (p < 0.001) were less likely (OR < 1) to receive brain radiotherapy as part of the first course of treatment. Conclusions: While insurance status and setting were not significantly associated with the use of brain radiotherapy, facility type was. Further research is needed to evaluate whether this is a true disparity in medical practice, or the differences can be explained by characteristics of the patient population undocumented by the NCDB (e.g. severity of brain metastasis). Additionally, patients with larger primary tumors were less likely to receive brain radiation as part of the first course of treatment, which may reflect the need for local therapy prior to treating metastatic sites.

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Roles of the CXCL8-CXCR1/2 Axis in the Tumor Microenvironment and Immunotherapy

Molecules ◽

10.3390/molecules27010137 ◽

2021 ◽

Vol 27 (1) ◽

pp. 137

Author(s):

Zhi-Jian Han ◽

Yang-Bing Li ◽

Lu-Xi Yang ◽

Hui-Juan Cheng ◽

Xin Liu ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Progression ◽

Immune Cells ◽

Epithelial To Mesenchymal Transition ◽

Checkpoint Inhibitors ◽

Lymphatic Vessels ◽

Cell Types ◽

Mesenchymal Transition ◽

Development Of Resistance ◽

Immunosuppressive Cells

In humans, Interleukin-8 (IL-8 or CXCL8) is a granulocytic chemokine with multiple roles within the tumor microenvironment (TME), such as recruiting immunosuppressive cells to the tumor, increasing tumor angiogenesis, and promoting epithelial-to-mesenchymal transition (EMT). All of these effects of CXCL8 on individual cell types can result in cascading alterations to the TME. The changes in the TME components such as the cancer-associated fibroblasts (CAFs), the immune cells, the extracellular matrix, the blood vessels, or the lymphatic vessels further influence tumor progression and therapeutic resistance. Emerging roles of the microbiome in tumorigenesis or tumor progression revealed the intricate interactions between inflammatory response, dysbiosis, metabolites, CXCL8, immune cells, and the TME. Studies have shown that CXCL8 directly contributes to TME remodeling, cancer plasticity, and the development of resistance to both chemotherapy and immunotherapy. Further, clinical data demonstrate that CXCL8 could be an easily measurable prognostic biomarker in patients receiving immune checkpoint inhibitors. The blockade of the CXCL8-CXCR1/2 axis alone or in combination with other immunotherapy will be a promising strategy to improve antitumor efficacy. Herein, we review recent advances focusing on identifying the mechanisms between TME components and the CXCL8-CXCR1/2 axis for novel immunotherapy strategies.

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Metastatic brain tumours

10.1093/med/9780199651870.003.0019 ◽

2017 ◽

Author(s):

Matthias Preusser ◽

Gabriele Schackert ◽

Brigitta G. Baumert

Keyword(s):

Brain Metastasis ◽

Brain Tumours ◽

Median Overall Survival ◽

Checkpoint Inhibitors ◽

Whole Brain Radiotherapy ◽

Braf Inhibitors ◽

Survival Times ◽

Brain Radiotherapy ◽

Cancer Breast ◽

Clinical Challenge

Brain metastasis is a common clinical challenge in cancer patients, particularly those with lung cancer, breast cancer, and melanoma. The prognosis is poor, with median overall survival times measured in months for most patient populations. Established treatments include neurosurgical resection, radiotherapy (including stereotactic radiosurgery and stereotactic radiotherapy, whole-brain radiotherapy, and new radiation techniques), and supportive care measures. Recently, more and more targeted therapies such as EGFR inhibitors, HER2 antagonists, BRAF inhibitors, ALK inhibitors, and immune checkpoint inhibitors are demonstrating some efficacy in brain metastasis patients and should be considered in the clinical setting.

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Potential alteration of tumor microenvironments by β-mercaptoethanol

Future Oncology ◽

10.2217/fon-2020-0801 ◽

2020 ◽

Author(s):

Robert E Click

Keyword(s):

Molecular Weight ◽

Tumor Microenvironment ◽

Immune Checkpoint ◽

Tumor Antigens ◽

Checkpoint Inhibitors ◽

Survival Rates ◽

Suppressor Cells ◽

Low Molecular Weight ◽

Uptake Inhibition ◽

Tumor Microenvironments

The therapeutic effectiveness of immune checkpoint inhibitors in cancer patients is quite profound. However, it is generally accepted that further progress is curtailed by accompanying adverse events and by low cure rates linked to the tumor microenvironment. The multitudes of immune processes altered by low-molecular-weight thiols published over the past decades suggest they have potential to alter tumor microenvironment processes which could result in an increase in immune checkpoint inhibitor survival rates. Based on one of the most studied and most potent low-molecular-weight thiols, β-mercaptoethanol (BME), it is proposed that clinical assessment be undertaken to identify any BME benefits with relevance for proliferation/differentiation of immune cells, lymphocyte exhaustion, immunogenicity of tumor antigens and inactivation of suppressor cells/factors. The BME alterations projected to be most effective are: maintenance/replacement of glutathione in lymphocytes via facilitation of cysteine uptake, inhibition of suppressor cells/soluble factors and inactivation of free-radical, reactive oxygen species.

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The Role of Somatic Mutations on the Immune Response of the Tumor Microenvironment in Prostate Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22179550 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9550

Author(s):

Camila Morais Melo ◽

Thiago Vidotto ◽

Luiz Paulo Chaves ◽

William Lautert-Dutra ◽

Rodolfo Borges dos Reis ◽

...

Keyword(s):

Prostate Cancer ◽

Immune Response ◽

Tumor Microenvironment ◽

Somatic Mutations ◽

Checkpoint Inhibitors ◽

Molecular Genetic ◽

Cell Types ◽

T Cell Response ◽

Cancer Genes ◽

Regulatory Pathways

Immunotherapy has improved patient survival in many types of cancer, but for prostate cancer, initial results with immunotherapy have been disappointing. Prostate cancer is considered an immunologically excluded or cold tumor, unable to generate an effective T-cell response against cancer cells. However, a small but significant percentage of patients do respond to immunotherapy, suggesting that some specific molecular subtypes of this tumor may have a better response to checkpoint inhibitors. Recent findings suggest that, in addition to their function as cancer genes, somatic mutations of PTEN, TP53, RB1, CDK12, and DNA repair, or specific activation of regulatory pathways, such as ETS or MYC, may also facilitate immune evasion of the host response against cancer. This review presents an update of recent discoveries about the role that the common somatic mutations can play in changing the tumor microenvironment and immune response against prostate cancer. We describe how detailed molecular genetic analyses of the tumor microenvironment of prostate cancer using mouse models and human tumors are providing new insights into the cell types and pathways mediating immune responses. These analyses are helping researchers to design drug combinations that are more likely to target the molecular and immunological pathways that underlie treatment failure.

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Genomic and transcriptomic correlates of immunotherapy response within the tumor microenvironment of leptomeningeal metastases

Nature Communications ◽

10.1038/s41467-021-25860-5 ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Sanjay M. Prakadan ◽

Christopher A. Alvarez-Breckenridge ◽

Samuel C. Markson ◽

Albert E. Kim ◽

Robert H. Klein ◽

...

Keyword(s):

Tumor Microenvironment ◽

Single Cell ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Cell Types ◽

Malignant Cell ◽

Leptomeningeal Disease ◽

Two Phase ◽

Molecular Features ◽

Phase Ii Clinical Trials

AbstractLeptomeningeal disease (LMD) is a devastating complication of solid tumor malignancies, with dire prognosis and no effective systemic treatment options. Over the past decade, the incidence of LMD has steadily increased due to therapeutics that have extended the survival of cancer patients, highlighting the need for new interventions. To examine the efficacy of immune checkpoint inhibitors (ICI) in patients with LMD, we completed two phase II clinical trials. Here, we investigate the cellular and molecular features underpinning observed patient trajectories in these trials by applying single-cell RNA and cell-free DNA profiling to longitudinal cerebrospinal fluid (CSF) draws from enrolled patients. We recover immune and malignant cell types in the CSF, characterize cell behavior changes following ICI, and identify genomic features associated with relevant clinical phenomena. Overall, our study describes the liquid LMD tumor microenvironment prior to and following ICI treatment and demonstrates clinical utility of cell-free and single-cell genomic measurements for LMD research.

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Phenotypic shifts of tumor associated macrophages and STAT3 mediated suppression of myeloid derived suppressor cells drive sensitization of HER2+ tumor immunity

10.1101/2021.01.29.428708 ◽

2021 ◽

Author(s):

Dimitrios N. Sidiropoulos ◽

Christine Rafie ◽

Brian J. Christmas ◽

Emily F. Davis-Marcisak ◽

Gaurav Sharma ◽

...

Keyword(s):

Checkpoint Inhibitors ◽

Suppressor Cells ◽

Breast Tumors ◽

Cell Types ◽

Myeloid Derived Suppressor Cells ◽

Tumor Associated Macrophages ◽

Tumor Microenvironments ◽

Deacetylase Inhibitor ◽

M1 Phenotype ◽

Tumor Cell Killing

ABSTRACTUnderstanding how novel therapeutic combinations alter solid tumor microenvironments (TME) in immunosuppressive tumors such as breast cancer is essential to improve their responses to immune checkpoint inhibitors (ICIs). Entinostat, an oral histone deacetylase inhibitor (HDACi), has been shown to improve responses to ICIs in various tumor models with immunosuppressive TMEs, but the precise alterations induced by entinostat and mechanisms of synergy with ICIs remain unknown. Here, we employ single-cell RNA-sequencing on HER2 overexpressing breast tumors from mice treated with entinostat + ICIs to characterize these changes across cell types in the TME. This analysis demonstrates that treatment with entinostat induces a shift from a pro-tumor to an anti-tumor TME signature characterized predominantly by changes in the myeloid cells. Notably, myeloid-derived suppressor cells (MDSCs) are shifted toward the less suppressive granulocytic phenotype in association with reduced signaling through the STAT3 pathway. In addition, tumor-associated macrophages are shifted toward an anti-tumor M1 phenotype by epigenetic reprogramming. Overall, these entinostat-induced TME changes reduce immunosuppression and increase mechanisms of tumor cell killing to improve ICI responses and broaden the population of patients who could potentially benefit from immunotherapy.

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Genomic characterization of six virus-associated cancers identifies changes in the tumor microenvironment and altered genetic programming

10.1101/289900 ◽

2018 ◽

Author(s):

Frederick S. Varn ◽

Yue Wang ◽

Chao Cheng

Keyword(s):

Tumor Microenvironment ◽

Checkpoint Inhibitors ◽

Cell Types ◽

Cell Receptor ◽

The Cancer Genome Atlas ◽

Specific Gene ◽

Barr Virus ◽

Receptor Repertoire ◽

Epstein Barr ◽

Tumor Types

AbstractViruses affect approximately 20% of all human cancers and express immunogenic proteins that make these tumor types potent targets for immune checkpoint inhibitors. In this study, we apply computational tools to The Cancer Genome Atlas and other datasets to define how virus infection shapes the tumor microenvironment and genetic architecture of 6 virus-associated tumor types. Across cancers, the cellular composition of the tumor microenvironment varied based on viral status, with infected tumors often exhibiting increased infiltration of cytolytic cell types. Analyses of the infiltrating T cell receptor repertoire revealed that Epstein-Barr virus was associated with decreased diversity in multiple cancers, suggesting an antigen-driven immune response. Tissue-specific gene expression signatures capturing these virus-induced transcriptomic changes successfully predicted virus status in independent datasets and were associated with both immune- and proliferation-related features that were predictive of prognosis. The analyses presented suggest viruses have distinct effects in different tumors with implications for immunotherapy.

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Treatment of Alectinib in NSCLC With Brain Metastasis Patient Refractory to Radiotherapy After Resistance to Crizotinib: A Case Report and Literature Review

10.21203/rs.3.rs-342760/v1 ◽

2021 ◽

Author(s):

YUAN ZHOU ◽

Xianliang Zeng ◽

Songwei Sun ◽

Xiuli Chen ◽

Shuang Huang ◽

...

Keyword(s):

Brain Metastasis ◽

Liquid Biopsy ◽

Target Therapy ◽

Nsclc Patient ◽

Whole Brain Radiotherapy ◽

Alk Rearrangement ◽

Whole Brain ◽

Tissue Biopsy ◽

Brain Radiotherapy ◽

Alk Positive

Abstract Background: Brain metastasis is the common place of tumor recurrence after resistance to crizotinib. The therapeutic modes on brain metastasis of ALK-positive NSCLC require multidisciplinary approach, including target therapy, chemotherapy and radiotherapy. Until to nowadays, there isn`t optimal therapeutic recommendations for these patients. Radiotherapy is the vital treatment for brain metastasis.Case presentation: We reported one ALK-positive NSCLC patient with brain metastasis after crizotinib. ALK rearrangement wasn`t found in blood sample of the patient by NGS. According to NCCN guideline, we gave the patient whole brain radiotherapy. It was unexpected that the number of brain metastasis increased after whole brain radiotherapy. After that, the patient was empirically used alectinib after radiotherapy failure. It achieved unexpected success in our patient. Conclusions: We got some enlightenment form the patient. Firstly, liquid biopsy is complementary to tissue biopsy in NSCLC, mainly in EGFR mutation. However, ALK detection should use tissue biopsy as much as possible. Secondly, we suggest the brain metastasis patient of NSCLC use the second generation TKI, such as alectinib, ceritinib, after resistance to crizotinib whether ALKr is positive or negative in liquid biopsy. Lastly, we believe that combined radiotherapy with TKIs is an optimal mode in the BM patient of NSCLC after resistance to crizotinib.

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