Clinical Implications of Tumor-Infiltrating Immune Cells in Breast Cancer

Zhang, Shichao; Hu, Ziyi; Long, Ju; Zhu, Guiming; Wang, Yun; Jia, Yi; Zhou, Jing; Ouyang, Yu; Zeng, Zhu

doi:10.7150/jca.35901

Cited by 129 publications

(104 citation statements)

References 45 publications

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“…Cancer cells and cardiomyocytes were plated in 96-well flat-bottom plates at the density of 150,000 cells/well for 16 h. hPBMCs, a population of immune cells consisting of T cells, B cells, natural killer cells, dendritic cells, and monocytes [ 77 ] from healthy donors, were added at effector: target ratio 5:1 in the absence or presence of ipilimumab as described previously [ 78 , 79 ]; in fact, hPBMCs are conventionally used in cellular experiments of responsiveness to PD-1, PDL-1, or CTLA-4 blocking agents [ 80 , 81 , 82 ]. Co-culture of MCF7 or MDA-MB-231 cells or AC16 cells with hPBMCs mimics, respectively, the immune cell infiltration in breast cancer tissue (the immune infiltration of tumors is closely related to clinical outcomes in breast cancer patients [ 83 , 84 ]), as well as in myocardial tissue (patients treated with CTLA-4 blocking agents developed severe/fatal myocarditis which was likely a result of the lymphocytic infiltration of lymphocytes [ 85 , 86 ]).…”

Section: Methodsmentioning

confidence: 99%

NLRP3 as Putative Marker of Ipilimumab-Induced Cardiotoxicity in the Presence of Hyperglycemia in Estrogen-Responsive and Triple-Negative Breast Cancer Cells

Quagliariello

Laurentiis

Cocco

et al. 2020

IJMS

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Hyperglycemia, obesity and metabolic syndrome are negative prognostic factors in breast cancer patients. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, achieving unprecedented efficacy in multiple malignancies. However, ICIs are associated with immune-related adverse events involving cardiotoxicity. We aimed to study if hyperglycemia could affect ipilimumab-induced anticancer efficacy and enhance its cardiotoxicity. Human cardiomyocytes and estrogen-responsive and triple-negative breast cancer cells (MCF-7 and MDA-MB-231 cell lines) were exposed to ipilimumab under high glucose (25 mM); low glucose (5.5 mM); high glucose and co-administration of SGLT-2 inhibitor (empagliflozin); shifting from high glucose to low glucose. Study of cell viability and the expression of new putative biomarkers of cardiotoxicity and resistance to ICIs (NLRP3, MyD88, cytokines) were quantified through ELISA (Cayman Chemical) methods. Hyperglycemia during treatment with ipilimumab increased cardiotoxicity and reduced mortality of breast cancer cells in a manner that is sensitive to NLRP3. Notably, treatment with ipilimumab and empagliflozin under high glucose or shifting from high glucose to low glucose reduced significantly the magnitude of the effects, increasing responsiveness to ipilimumab and reducing cardiotoxicity. To our knowledge, this is the first evidence that hyperglycemia exacerbates ipilimumab-induced cardiotoxicity and decreases its anticancer efficacy in MCF-7 and MDA-MB-231 cells. This study sets the stage for further tests on other breast cancer cell lines and primary cardiomyocytes and for preclinical trials in mice aimed to decrease glucose through nutritional interventions or administration of gliflozines during treatment with ipilimumab.

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Section: Methodsmentioning

confidence: 99%

NLRP3 as Putative Marker of Ipilimumab-Induced Cardiotoxicity in the Presence of Hyperglycemia in Estrogen-Responsive and Triple-Negative Breast Cancer Cells

Quagliariello

Laurentiis

Cocco

et al. 2020

IJMS

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“…example, higher TAM density correlates with both a worse prognosis and a higher probability of distant metastases. 15,16 Closer to home for the neurosurgeon, TAM may play a role in the progression of central nervous system (CNS) tumors, both malignant and benign. TAM are a feature of the glioblastoma microenvironment and numerous studies have demonstrated an association between a higher proportion of tumor-promoting, M2 (see below for definition) macrophages and a worse prognosis in affected patients.…”

Section: The Inflammatory Microenvironment In Vs: Evidence Emergesmentioning

confidence: 99%

Beyond Antoni: A Surgeon's Guide to the Vestibular Schwannoma Microenvironment

Hannan

Lewis

O’Leary

et al. 2020

J Neurol Surg B Skull Base

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Introduction Vestibular schwannomas (VS) are histologically benign tumors arising from cranial nerve VIII. Far from a homogenous proliferation of Schwann cells, mounting evidence has highlighted the complex nature of the inflammatory microenvironment in these tumors. Methods A review of the literature pertaining to inflammation, inflammatory molecular pathways, and immune-related therapeutic targets in VS was performed. Relevant studies published up to June 2020 were identified based on a literature search in the PubMed and MEDLINE databases and the findings were synthesized into a concise narrative review of the topic. Results The VS microenvironment is characterized by a dense infiltrate of inflammatory cells, particularly macrophages. Significantly higher levels of immune cell infiltration are observed in growing versus static tumors, and there is a demonstrable interplay between inflammation and angiogenesis in growing VS. While further mechanistic studies are required to ascertain the exact role of inflammation in angiogenesis, tumor growth, and Schwann cell control, we are beginning to understand the key molecular pathways driving this inflammatory microenvironment, and how these processes can be monitored and targeted in vivo. Conclusion Observational research has revealed a complex and heterogeneous tumor microenvironment in VS. The functional landscape and roles of macrophages and other immune cells in the VS inflammatory infiltrate are, however, yet to be established. The antiangiogenic drug bevacizumab has shown the efficacy of targeted molecular therapies in VS and there is hope that agents targeting another major component of the VS microenvironment, inflammation, will also find a place in their future management.

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“…From the results of the correlation coefficient, we can conclude that there was a strong correlation between monocytes and both DFS (r = 0.41) and OS (r = 0.23). Similarly, Zhang et al [42] found that infiltrating immune cells were associated with survival, therapeutic responses and prognosis of breast cancer patients and monocytes were decreased in cancer patients with higher-grade tumors. From the perspective of clusters to further explore the association between AS events with clinical data, tumor mutation burden and immune features.…”

Section: Discussionmentioning

confidence: 89%

Systematic profiling of alternative splicing in Helicobacter pylori-negative gastric cancer and their clinical significance

Liu

et al. 2020

Cancer Cell Int

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Background: Alternative splicing (AS) may cause structural and functional variations in the protein to promote the proliferation of tumor cells. However, there is no comprehensive analysis of the clinical significance of AS in Helicobacter pylori-negative gastric cancer (HP − GC). Methods: The clinical, gene expression profile data and AS events of 138 HP − GC patients were obtained from the database named the cancer genome atlas. Differently expressed AS (DEAS) events were determined by a comparison of the PSI values between HP − GC samples and adjacent normal samples. Unsupervised clustering analysis, proportional regression and Kaplan-Meier analysis were used to explore the association between clinical data and immune features and to establish two nomograms about the prognosis of HP − GC. Finally, splicing networks were constructed using Cytoscape. Results: A total of 48141 AS events and 1041 DEAS events were found in HP − GC. Various functions and pathways of DEAS events parent genes were enriched, such as cell-substrate junction, cell leading edge, focal adhension, and AMPK signaling. Seven overall survival (OS)-related and seven disease-free survival (DFS)-related AS events were used to construct the prognostic signatures. Based on the independent prognostic factors, two nomograms were established and showed excellent performance. Then, splicing regulatory networks among the correlations suggested that splicing factors were significantly associated with prognostic DEASs. Finally, the unsupervised clustering analysis revealed that DEAS-based clusters were associated with clinical characteristics, tumor microenvironment, tumor mutation burden, and immune features. Conclusion: Seven OS-related and seven DFS-related AS events have been found to be correlated with the prognosis of HP − GC and can be used as prognostic factors to establish an effective nomogram.

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Clinical Implications of Tumor-Infiltrating Immune Cells in Breast Cancer

Cited by 129 publications

References 45 publications

NLRP3 as Putative Marker of Ipilimumab-Induced Cardiotoxicity in the Presence of Hyperglycemia in Estrogen-Responsive and Triple-Negative Breast Cancer Cells

NLRP3 as Putative Marker of Ipilimumab-Induced Cardiotoxicity in the Presence of Hyperglycemia in Estrogen-Responsive and Triple-Negative Breast Cancer Cells

Beyond Antoni: A Surgeon's Guide to the Vestibular Schwannoma Microenvironment

Systematic profiling of alternative splicing in Helicobacter pylori-negative gastric cancer and their clinical significance

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