The immune system in cancer metastasis: friend or foe?

Janssen, Louise M.E.; Ramsay, Emma E.; Logsdon, Craig D.; Overwijk, Willem W.

doi:10.1186/s40425-017-0283-9

Cited by 234 publications

(199 citation statements)

References 126 publications

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“…It is unclear how the complex interplay between tumor cells and the tumor microenvironment (TME) and their interactions affect treatment outcome in metastatic cancer (Kitamura, Qian, and Pollard 2015;Janssen et al 2017;Robinson et al 2017). Investigating this interplay in an advanced disease setting is complicated by the difficulty of obtaining multiple-site tumor samples and the finding that different tumors within the same individual can harbor 30 distinct immune microenvironments (Sridharan et al 2016;Jiménez-Sánchez et al 2017a;Reuben et al 2017;A.…”

Section: Introduction 25mentioning

confidence: 99%

Unraveling Tumor-Immune Heterogeneity in Advanced Ovarian Cancer Uncovers Immunogenic Effect of Chemotherapy

Jiménez-Sánchez

Cybulska

LaVigne

et al. 2018

Preprint

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In metastatic cancer, the role of heterogeneity at the tumor-immune microenvironment, its molecular underpinnings and clinical relevance remain largely unexplored. To understand tumor-immune dynamics at baseline and upon chemotherapy treatment, we performed unbiased pathway and cell type-specific immunogenomics analysis of treatment-naive (38 5 samples from 8 patients) and paired chemotherapy treated (80 paired samples from 40 patients) high-grade serous ovarian cancer (HGSOC) samples. Whole transcriptome analysis and imagebased quantification of T cells from treatment-naive tumors revealed ubiquitous variability in immune signaling and distinct immune microenvironments co-existing within the same individuals and within tumor deposits at diagnosis. To systematically explore cell type 10 composition of the tumor microenvironment using bulk mRNA, we derived consensus immune and stromal cell gene signatures by intersecting state-of-the-art deconvolution methods, providing improved accuracy and sensitivity when compared to HGSOC immunostaining and leukocyte methylation data sets. Cell-type deconvolution and pathway analyses revealed that Myc and Wnt signaling associate with immune cell exclusion in untreated HGSOC. To evaluate 15 the effect of chemotherapy on the intrinsic tumor-immune heterogeneity, we compared sitematched and site-unmatched tumors before and after neoadjuvant chemotherapy.Transcriptomic and T-cell receptor sequencing analyses showed that site-matched samples had increased cytotoxic immune activation and oligoclonal expansion of T cells after chemotherapy, which was not seen in site-unmatched samples where heterogeneity could not be accounted 20for. These results demonstrate that the tumor-immune interface in advanced HGSOC is intrinsically heterogeneous, and thus requires site-specific analysis to reliably unmask the impact of therapy on the tumor-immune microenvironment. 1050 Conceptualization [Ideas; formulation or evolution of overarching research goals and aims] AS, AJS, MLM, ES Data curation [Management activities to annotate (produce metadata), scrub data and maintain research data (including software code, where necessary for interpreting the data itself) for 1055 initial use and later re-use] AJS, KL, PC Formal analysis [Application of statistical, mathematical, computational, or other formal techniques to analyse or synthesize study data] 1060 AJS Funding acquisition [Acquisition of the financial support for the project leading to this publication] AV, ES, AS, MLM 1065 Investigation [Conducting a research and investigation process, specifically performing the experiments, or data/evidence collection] PC, KL, TW, YM, IN, BW, DC, ES 1070 50 Methodology [Development or design of methodology; creation of models] ES Project administration [Management and coordination responsibility for the research activity planning and execution] 1075 AS, MLM, ES Resources [Provision of study materials, reagents, materials, patients, laboratory samples, animals, instrumentation, computing resources, or other a...

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Section: Introduction 25mentioning

confidence: 99%

Unraveling Tumor-Immune Heterogeneity in Advanced Ovarian Cancer Uncovers Immunogenic Effect of Chemotherapy

Jiménez-Sánchez

Cybulska

LaVigne

et al. 2018

Preprint

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“…An ability to escape the immune response is important for cancer cells to survive in circulation and form metastasis in distant organs (Janssen et al, 2017;Blomberg et al, 2018). In our previous study, we found that AGC1-KD cells have lower cytosolic NAD + /NADH ratio and are less glycolytic (Alkan et al, 2018).…”

Section: Genes Related To Aldh1l1 Metabolism Are Deregulated In Agc1-mentioning

confidence: 93%

Loss of malate-aspartate shuttle component SLC25A12 induces pulmonary metastasis

Alkan

Vesely

Hackl

et al. 2020

Preprint

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Background: Aspartate biosynthesis and its delivery to the cytosol can be crucial for tumor growth in vivo.However, the impact of aspartate synthesis on metastasis has not been studied. We previously described that loss-of-aspartate glutamate carrier 1 (SLC25A12 or AGC1), an important component of the malateaspartate shuttle, impairs cytosolic aspartate levels, NAD + /NADH ratio, mitochondrial respiration, and tumor growth. Here, we report the impact of AGC1-knockdown on metastasis.Results: AGC1 expression is positively correlated with worse patient prognosis in many cancers. AGC1knockdown in mouse lung carcinoma and melanoma cell lines leads to increased pulmonary metastasis following subcutaneous or intravenous injections, respectively. On the other hand, conventional in vitro metastasis assays show no indication of increased metastasis capacity of AGC1-knockdown cells. Conclusion:This study highlights that certain branches of metabolism impact tumor growth and tumor metastasis differently. In addition, it also argues that commonly known metastasis indicators, including EMT genes, cell migration, or colony formation do not always reflect the metastatic capacity in vivo.

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“…TGFß1 expression is increased in the tumor epithelial cells of Smad4 −/− SCCs, and TGFß1 overexpression was associated with increased infiltration of granulocytes, macrophages, T cells, and Th17 cells in the tumor microenvironment . Tumor‐associated granulocytes, macrophages, and regulatory T cells (Tregs) can each block CD8+ T cell infiltration to promote tumor progression . Tregs can also block functional CD8+ and NK cells from attacking circulating metastatic cancer cells .…”

Section: Tumor Microenvironment and Progression Of Smad4 Deficient Sccsmentioning

confidence: 99%

“…6 Tumor-associated granulocytes, macrophages, and regulatory T cells (Tregs) can each block CD8+ T cell infiltration to promote tumor progression. 53,54 Tregs can also block functional CD8+ and NK cells from attacking circulating metastatic cancer cells. 53 Th17 cells play a controversial role in tumor immunity to either suppress or promote tumor progression depending on the malignancy.…”

Section: F I G U R E 1 Normal Versus Deficient Smad4 Signaling a Smad4mentioning

confidence: 99%

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Lessons learned from SMAD4 loss in squamous cell carcinomas

Young

Wang

2019

Molecular Carcinogenesis

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SMAD4 is a potent tumor suppressor and the primary mediator of the TGFß signaling pathway. SMAD4 genetic loss is frequent in squamous cell carcinomas (SCCs). Reports of SMAD4 expression in SCCs vary significantly possibly due to inter-tumor heterogeneity or technical reasons. SMAD4 loss is an initiation event for SCCs. In tumor epithelial cells, SMAD4 mutant SCCs commonly present with increased proliferation, decreased apoptosis, and “Brca-like” genomic instability associated with DNA repair defects. SMAD4 loss also plays a role in expansion of cancer stem cells (CSC). Epithelial SMAD4 loss causes overexpression of TGFß which is released into the tumor microenvironment and contributes to SCC progression through pro-inflammatory and immune evasive mechanisms. SMAD4 loss, while not directly targetable, is associated with multiple targetable pathways that require further studies. Altogether, SMAD4 loss is a potential biomarker in SCCs that should be further studied to gain insight for prognosis and therapeutic approaches to potentially guide future clinical trials and improve SCC patient outcomes.

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The immune system in cancer metastasis: friend or foe?

Cited by 234 publications

References 126 publications

Unraveling Tumor-Immune Heterogeneity in Advanced Ovarian Cancer Uncovers Immunogenic Effect of Chemotherapy

Unraveling Tumor-Immune Heterogeneity in Advanced Ovarian Cancer Uncovers Immunogenic Effect of Chemotherapy

Loss of malate-aspartate shuttle component SLC25A12 induces pulmonary metastasis

Lessons learned from SMAD4 loss in squamous cell carcinomas

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