scholarly journals Cancer stemness, intratumoral heterogeneity, and immune response across cancers

2018 ◽  
Author(s):  
Alex Miranda ◽  
Phineas T Hamilton ◽  
Allen W Zhang ◽  
Etienne Becht ◽  
Artur Mezheyeuski ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Immune Cell ◽  
Antigen Expression ◽  
Therapy Resistance ◽  
Intratumoral Heterogeneity ◽  
Type I ◽  
Interferon Signaling ◽  
Cancer Stemness ◽  
Tumor Phenotype ◽  
The Impact

SummaryRegulatory programs that control the function of stem cells are active in cancer and confer properties that promote progression and therapy resistance. However, the impact of a stem cell-like tumor phenotype (“sternness”) on the immunological properties of cancer has not been systematically explored. Using gene expression-based metrics, we evaluate the association of stemness with immune cell infiltration and genomic, transcriptomic, and clinical parameters across 21 solid cancers. We find pervasive negative associations between cancer stemness and anticancer immunity. This occurs despite high stemness cancers exhibiting increased mutation load, cancer-testis antigen expression, and intratumoral heterogeneity. Stemness was also strongly associated with cell-intrinsic suppression of endogenous retroviral expression and type I interferon signaling and increased expression of several therapeutically accessible signaling pathways. Thus, stemness is not only a fundamental process in cancer progression but may represent a unifying mechanism linking antigenicity, intratumoral heterogeneity, and immune suppression across cancers.

scholarly journals Cancer stemness, intratumoral heterogeneity, and immune response across cancers

2019 ◽  
Vol 116 (18) ◽  
pp. 9020-9029 ◽  
Author(s):  
Alex Miranda ◽  
Phineas T. Hamilton ◽  
Allen W. Zhang ◽  
Swetansu Pattnaik ◽  
Etienne Becht ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Immune Cell ◽  
Antigen Expression ◽  
Therapy Resistance ◽  
Intratumoral Heterogeneity ◽  
Endogenous Retroviruses ◽  
Type I ◽  
Cancer Stemness ◽  
Tumor Phenotype ◽  
The Impact

Regulatory programs that control the function of stem cells are active in cancer and confer properties that promote progression and therapy resistance. However, the impact of a stem cell-like tumor phenotype (“stemness”) on the immunological properties of cancer has not been systematically explored. Using gene-expression–based metrics, we evaluated the association of stemness with immune cell infiltration and genomic, transcriptomic, and clinical parameters across 21 solid cancers. We found pervasive negative associations between cancer stemness and anticancer immunity. This occurred despite high stemness cancers exhibiting increased mutation load, cancer-testis antigen expression, and intratumoral heterogeneity. Stemness was also strongly associated with cell-intrinsic suppression of endogenous retroviruses and type I IFN signaling, and increased expression of multiple therapeutically accessible immunosuppressive pathways. Thus, stemness is not only a fundamental process in cancer progression but may provide a mechanistic link between antigenicity, intratumoral heterogeneity, and immune suppression across cancers.

scholarly journals The Role of Cancer-Associated Fibroblasts in Tumor Progression

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1399
Author(s):  
Rushikesh S. Joshi ◽  
Samanvi S. Kanugula ◽  
Sweta Sudhir ◽  
Matheus P. Pereira ◽  
Saket Jain ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Immune Cell ◽  
Systemic Disease ◽  
Genomic Medicine ◽  
Therapeutic Targets ◽  
Therapy Resistance ◽  
Cancer Associated Fibroblasts ◽  
Breast Cancers

In the era of genomic medicine, cancer treatment has become more personalized as novel therapeutic targets and pathways are identified. Research over the past decade has shown the increasing importance of how the tumor microenvironment (TME) and the extracellular matrix (ECM), which is a major structural component of the TME, regulate oncogenic functions including tumor progression, metastasis, angiogenesis, therapy resistance, and immune cell modulation, amongst others. Within the TME, cancer-associated fibroblasts (CAFs) have been identified in several systemic cancers as critical regulators of the malignant cancer phenotype. This review of the literature comprehensively profiles the roles of CAFs implicated in gastrointestinal, endocrine, head and neck, skin, genitourinary, lung, and breast cancers. The ubiquitous presence of CAFs highlights their significance as modulators of cancer progression and has led to the subsequent characterization of potential therapeutic targets, which may help advance the cancer treatment paradigm to determine the next generation of cancer therapy. The aim of this review is to provide a detailed overview of the key roles that CAFs play in the scope of systemic disease, the mechanisms by which they enhance protumoral effects, and the primary CAF-related markers that may offer potential targets for novel therapeutics.

scholarly journals A bi-directional dialog between vascular cells and monocytes/macrophages regulates tumor progression

2021 ◽  
Author(s):  
Victor Delprat ◽  
Carine Michiels
Keyword(s):  
Tumor Progression ◽  
Cancer Progression ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
The Body ◽  
Vascular Cells ◽  
Tumor Associated Macrophage ◽  
Immune Cell Activation ◽  
The Impact

AbstractCancer progression largely depends on tumor blood vessels as well on immune cell infiltration. In various tumors, vascular cells, namely endothelial cells (ECs) and pericytes, strongly regulate leukocyte infiltration into tumors and immune cell activation, hence the immune response to cancers. Recently, a lot of compelling studies unraveled the molecular mechanisms by which tumor vascular cells regulate monocyte and tumor-associated macrophage (TAM) recruitment and phenotype, and consequently tumor progression. Reciprocally, TAMs and monocytes strongly modulate tumor blood vessel and tumor lymphatic vessel formation by exerting pro-angiogenic and lymphangiogenic effects, respectively. Finally, the interaction between monocytes/TAMs and vascular cells is also impacting several steps of the spread of cancer cells throughout the body, a process called metastasis. In this review, the impact of the bi-directional dialog between blood vascular cells and monocytes/TAMs in the regulation of tumor progression is discussed. All together, these data led to the design of combinations of anti-angiogenic and immunotherapy targeting TAMs/monocyte whose effects are briefly discussed in the last part of this review.

scholarly journals Type I Interferon Signaling Prevents Hepatitis B Virus-Specific T Cell Responses by Reducing Antigen Expression

2018 ◽  
Vol 92 (23) ◽  
Author(s):  
Keigo Kawashima ◽  
Masanori Isogawa ◽  
Susumu Hamada-Tsutsumi ◽  
Ian Baudi ◽  
Satoru Saito ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
Type I Interferon ◽  
T Cell Responses ◽  
Antigen Expression ◽  
Type I ◽  
Interferon Signaling ◽  
Cell Responses ◽  
B Virus

ABSTRACT Robust virus-specific CD8+ T cell responses are required for the clearance of hepatitis B virus (HBV). However, the factors that determine the magnitude of HBV-specific CD8+ T cell responses are poorly understood. To examine the impact of genetic variations of HBV on HBV-specific CD8+ T cell responses, we introduced three HBV clones (Aa_IND [Aa], C_JPN22 [C22], and D_IND60 [D60]) that express various amounts of HBV antigens into the livers of C57BL/6 (B6) (H-2b) mice and B10.D2 (H-2d) mice. In B6 mice, clone C22 barely induced HBV-specific CD8+ T cell responses and persisted the longest, while clone D60 elicited strong HBV-specific CD8+ T cell responses and was rapidly cleared. These differences between HBV clones largely diminished in H-2d mice. Interestingly, the magnitude of HBV-specific CD8+ T cell responses in B6 mice was associated with the HB core antigen expression level during the early phase of HBV transduction. Surprisingly, robust HBV-specific CD8+ T cell responses to clone C22 were induced in interferon-α/β receptor-deficient (IFN-αβR–/–) (H-2b) mice. The induction of HBV-specific CD8+ T cell responses to C22 in IFN-αβR–/– mice reflects enhanced HBV antigen expression because the suppression of antigen expression by HBV-specific small interfering RNA (siRNA) attenuated HBV-specific T cell responses in IFN-αβR–/– mice and prolonged HBV expression. Collectively, these results suggest that HBV genetic variation and type I interferon signaling determine the magnitude of HBV-specific CD8+ T cell responses by regulating the initial antigen expression levels. IMPORTANCE Hepatitis B virus (HBV) causes acute and chronic infection, and approximately 240 million people are chronically infected with HBV worldwide. It is generally believed that virus-specific CD8+ T cell responses are required for the clearance of HBV. However, the relative contributions of genetic variation and innate immune responses to the induction of HBV-specific CD8+ T cell responses are not fully understood. In this study, we discovered that different clearance rates between HBV clones after hydrodynamic transduction were associated with the magnitude of HBV-specific CD8+ T cell responses and initial HB core antigen expression. Surprisingly, type I interferon signaling negatively regulated HBV-specific CD8+ T cell responses by reducing early HBV antigen expression. These results show that the magnitude of the HBV-specific CD8+ T cell response is regulated primarily by the initial antigen expression level.

scholarly journals Type I Interferon Signaling Drives Microglial Dysfunction and Senescence in Human iPSC Models of Down Syndrome and Alzheimers Disease

2021 ◽  
Author(s):  
Mengmeng Jin ◽  
Ranji Xu ◽  
Mahabub Maraj Alam ◽  
Ziyuan Ma ◽  
Sining Zhu ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Brain Development ◽  
Type I Interferon ◽  
Chromosome 21 ◽  
Type I ◽  
Chimeric Mouse ◽  
Interferon Signaling ◽  
Alzheimers Disease ◽  
Human Microglia ◽  
The Impact

Microglia are critical for brain development and play a central role in Alzheimers disease (AD) etiology. Down syndrome (DS), also known as trisomy 21, is the most common genetic origin of intellectual disability and the most common risk factor for AD. Surprisingly, little information is available on the impact of trisomy of human chromosome 21 (Hsa21) on microglia in DS brain development and AD in DS (DSAD). Using our new induced pluripotent stem cell (iPSC)-based human microglia-containing cerebral organoid and chimeric mouse brain models, here we report that DS microglia exhibit enhanced synaptic pruning function during brain development. Consequently, electrophysiological recordings demonstrate that DS microglial mouse chimeras show impaired synaptic neurotransmission, as compared to control microglial chimeras. Upon being exposed to human brain tissue-derived soluble pathological tau, DS microglia display dystrophic phenotypes in chimeric mouse brains, recapitulating microglial responses seen in human AD and DSAD brain tissues. Further flow cytometry, single-cell RNA-sequencing, and immunohistological analyses of chimeric mouse brains demonstrate that DS microglia undergo cellular senescence and exhibit elevated type I interferon signaling after being challenged by pathological tau. Mechanistically, we find that shRNA-mediated knockdown of Hsa21encoded type I interferon receptor genes, IFNARs, rescues the defective DS microglial phenotypes both during brain development and in response to pathological tau. Our findings provide first in vivo evidence supporting a paradigm shifting theory that human microglia respond to pathological tau by exhibiting accelerated senescence and dystrophic phenotypes. Our results further suggest that targeting IFNARs may improve microglial functions during DS brain development and prevent human microglial senescence in DS individuals with AD.

Targeting epithelial–mesenchymal plasticity in cancer: clinical and preclinical advances in therapy and monitoring

2017 ◽  
Vol 474 (19) ◽  
pp. 3269-3306 ◽  
Author(s):  
Sugandha Bhatia ◽  
James Monkman ◽  
Alan Kie Leong Toh ◽  
Shivashankar H. Nagaraj ◽  
Erik W. Thompson
Keyword(s):  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Therapy Resistance ◽  
Carcinoma Cells ◽  
Related Phenomenon ◽  
Mesenchymal Transition ◽  
Control Loops ◽  
Monitoring Strategies ◽  
The Impact ◽  
Ability To Drive

The concept of epithelial–mesenchymal plasticity (EMP), which describes the dynamic flux within the spectrum of phenotypic states that invasive carcinoma cells may reside, is being increasingly recognised for its role in cancer progression and therapy resistance. The myriad of events that are able to induce EMP, as well as the more recently characterised control loops, results in dynamic transitions of cancerous epithelial cells to more mesenchymal-like phenotypes through an epithelial–mesenchymal transition (EMT), as well as the reverse transition from mesenchymal phenotypes to an epithelial one. The significance of EMP, in its ability to drive local invasion, generate cancer stem cells and facilitate metastasis by the dissemination of circulating tumour cells (CTCs), highlights its importance as a targetable programme to combat cancer morbidity and mortality. The focus of this review is to consolidate the existing knowledge on the strategies currently in development to combat cancer progression via inhibition of specific facets of EMP. The prevalence of relapse due to therapy resistance and metastatic propensity that EMP endows should be considered when designing therapy regimes, and such therapies should synergise with existing chemotherapeutics to benefit efficacy. To further improve upon EMP-targeted therapies, it is imperative to devise monitoring strategies to assess the impact of such treatments on EMP-related phenomenon such as CTC burden, chemosensitivity/-resistance and micrometastasis in patients.

scholarly journals AB0034 PD-1 AGONISM INHIBITS ACTIVATION OF PLASMACYTOID DENDRITIC CELLS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1050.1-1050
Author(s):  
I. Banerjee ◽  
L. Edwards ◽  
P. Halvey ◽  
S. Alioto ◽  
D. Cluckley ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Cell ◽  
Plasmacytoid Dendritic Cells ◽  
Clinical Aspects ◽  
Immune Homeostasis ◽  
Type I ◽  
Immunoglobulin Gene ◽  
Human Pbmcs ◽  
Type I Ifn ◽  
The Impact

Background:T cell function is regulated by complex signaling networks of interconnected activators and inhibitors. Blockade of inhibitory receptors such as programmed death-1 (PD-1) has emerged as a novel treatment for multiple forms of cancer. One of the most common adverse events associated with blockade of the endogenous PD-1/PD-L1 pathway is the induction of autoimmune pathology in multiple tissues, demonstrating that PD-1 activation is necessary for normal immune homeostasis in humans (Kostine, et al., 2018). Given this body of clinical data, we sought to develop a PD-1 agonist antibody as a therapeutic approach to restore immune homeostasis in patients living with autoimmune diseases. PD-1 expression and function has been primarily described on T cells (Ishida, et al., 1992), with additional data available from several other immune cell populations (Ohaegbulam, et al., 2015).Objectives:To study the effect of PD-1 agonism on plasmacytoid dendritic cell (pDC) function.Methods:Human PBMCs stimulated with or without toll-like receptor (TLR)-9 agonist, CpG were analyzed by flow cytometry for PD-1 expression on immune cell subsets. To assess the impact of PD-1 agonist on pDC function human PBMCs were activated by CpG in the presence or absence of PD-1 agonist. Type-I interferon (IFN) levels were quantified using ELISA from culture supernatants. The expression of interferon stimulated genes was analyzed by qPCR as a measure of type-I IFN activation.Results:We have discovered that TLR9 activation can induce PD-1 expression on plasmacytoid dendritic cells, which has not been previously reported. Further, we have demonstrated that PD-1 agonism inhibits TLR9-mediated activation and the effector functions of plasmacytoid dendritic cells.Conclusion:These data suggest the potential of PD-1 as a target for regulating diseases with pathology generated by type-I IFN.References:[1]Ishida, Y., Agata, Y., Shihibahara, K., & Honjo, T. (1992). Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J., 11(11):3887-95.[2]Kostine, M., Rouxel, L., Barnetche, T., Veillon, R., Martin, F., Dutriaux, C., . . . Schaeverbeke, T. (2018). Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study. Annual Rheumatic Disease, 77(3):393-398.[3]Ohaegbulam, K. C., Assal, A., Lazar-Molnar, E., Yao, Y., & Zang, X. (2015). Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends in Molecular Medicine, 21(1); 24-33.Disclosure of Interests:Ishita Banerjee Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Lindsay Edwards Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Patrick Halvey Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Salvatore Alioto Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, David Cluckley Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Caitlin Mitchell Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Christopher Cox Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Emily Lurier Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Michael Cianci Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Soumya Bengeri Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Susmita Borthakur Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Katalin Kis-Toth Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Nathan Higginson-Scott Shareholder of: Pandion Therapeutics, Consultant of: Biotech Companies, Employee of: Pandion Therapeutics, Jo Viney Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Kevin L. Otipoby Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics

scholarly journals Manipulation of Type I Interferon Signaling by HIV and AIDS-Associated Viruses

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Buyuan He ◽  
James T. Tran ◽  
David Jesse Sanchez
Keyword(s):  
Viral Infections ◽  
Type I Interferon ◽  
Antiviral Effect ◽  
Hiv And Aids ◽  
Type I Interferons ◽  
Type I ◽  
Interferon Signaling ◽  
Chronic Viral Infections ◽  
Pathogenic Viruses ◽  
The Impact

Type I Interferons were first described for their profound antiviral abilities in cell culture and animal models, and later, they were translated into potent antiviral therapeutics. However, as additional studies into the function of Type I Interferons progressed, it was also seen that pathogenic viruses have coevolved to encode potent mechanisms allowing them to evade or suppress the impact of Type I Interferons on their replication. For chronic viral infections, such as HIV and many of the AIDS-associated viruses, including HTLV, HCV, KSHV, and EBV, the clinical efficacy of Type I Interferons is limited by these mechanisms. Here, we review some of the ways that HIV and AIDS-associated viruses thrive in Type I Interferon-rich environments via mechanisms that block the function of this important antiviral cytokine. Overall, a better understanding of these mechanisms creates avenues to better understand the innate immune response to these viruses as well as plan the development of antivirals that would allow the natural antiviral effect of Type I Interferons to manifest during these infections.

scholarly journals SARS-CoV-2 infection in the lungs of human ACE2 transgenic mice causes severe inflammation, immune cell infiltration, and compromised respiratory function

2020 ◽  
Author(s):  
Emma S. Winkler ◽  
Adam L. Bailey ◽  
Natasha M. Kafai ◽  
Sharmila Nair ◽  
Broc T. McCune ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Lung Disease ◽  
Immune Cell ◽  
Gene Promoter ◽  
Type I ◽  
Sequencing Analysis ◽  
Interferon Signaling ◽  
Activated T Cells ◽  
Mechanistic Basis ◽  
Activation Pathways

ABSTRACTSevere Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) emerged in late 2019 and has spread worldwide resulting in the Coronavirus Disease 2019 (COVID-19) pandemic. Although animal models have been evaluated for SARS-CoV-2 infection, none have recapitulated the severe lung disease phenotypes seen in hospitalized human cases. Here, we evaluate heterozygous transgenic mice expressing the human ACE2 receptor driven by the epithelial cell cytokeratin-18 gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lung tissues with additional spread to other organs. Remarkably, a decline in pulmonary function, as measured by static and dynamic tests of respiratory capacity, occurs 4 days after peak viral titer and correlates with an inflammatory response marked by infiltration into the lung of monocytes, neutrophils, and activated T cells resulting in pneumonia. Cytokine profiling and RNA sequencing analysis of SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with prominent signatures of NF-kB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection recapitulates many features of severe COVID-19 infection in humans and can be used to define the mechanistic basis of lung disease and test immune and antiviral-based countermeasures.

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