Multispectral imaging for quantitative and compartment‐specific immune infiltrates reveals distinct immune profiles that classify lung cancer patients

Mezheyeuski, Artur; Bergsland, Christian H.; Backman, Max; Djureinovic, Dijana; Sjöblom, Tobias; Bruun, Jarle; Micke, Patrick

doi:10.1002/path.5026

Cited by 155 publications

(143 citation statements)

References 61 publications

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“…We next evaluated this relationship in a cohort of 35 lung cancer patients with matched RNA-sequencing and IHC-based quantitation of immune cell infiltrates (Mezheyeuski et al, 2018). For consistency with the above analysis, we calculated the infiltration of T cells by summing previously calculated CD4+ and CD8+ cell fractions.…”

Section: Stemness Associates With Immunologically Cold Cancers Measurmentioning

confidence: 99%

“…For correlations between stemness scores and IHC-based immune cell counts, immune cell infiltration data were provided by the authors of the respective studies (Becht et al, 2016;Mezheyeuski et al, 2018). Overlapping expression data (microarray or RNAsequencing) was obtained from the gene expression omnibus (GEO: GSE39582; GEO:…”

Section: Experimental Models and Subject Detailsmentioning

confidence: 99%

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Cancer stemness, intratumoral heterogeneity, and immune response across cancers

Miranda¹,

Hamilton²,

Zhang

et al. 2018

Preprint

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110

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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 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.

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Section: Stemness Associates With Immunologically Cold Cancers Measurmentioning

confidence: 99%

Section: Experimental Models and Subject Detailsmentioning

confidence: 99%

Cancer stemness, intratumoral heterogeneity, and immune response across cancers

Miranda¹,

Hamilton²,

Zhang

et al. 2018

Preprint

Self Cite

110

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“…We analyzed a TMA that contained 35 samples of independent glioblastoma patients and 5 samples of normal brain tissue, each in duplicate, generating 80 tissue cores per TMA (TMA GL806d; US Biomax, Derwood, MF, USA). Mutiplexed immunohistochemical analysis was previously described with the following adaptations (Mezheyeuski et al, 2018). TMA slides were deparaffinized in xylene, hydrated in graded alcohols, and fixed in neutral buffered formalin for 20 min.…”

Section: Multiplex Immunohistochemical Stainingmentioning

confidence: 99%

NOX4 regulates TGFβ-induced proliferation and self-renewal in glioblastoma stem cells

García-Gómez

Dadras²,

Bellomo³

et al. 2019

Preprint

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Glioblastoma (GBM) is the most aggressive and common glioma subtype with a median survival of 15 months after diagnosis. Current treatments have limited therapeutic efficacy, thus more effective approaches are needed. The glioblastoma tumoral mass is characterized by a small cellular subpopulation, the Glioblastoma stem cells (GSCs), which has been held accountant for initiation, invasion, proliferation, relapse and resistance to chemo-and radiotherapy. Targeted therapies against GSCs are crucial, and so is the understanding of the molecular mechanisms that govern the GSCs.Transforming growth factor β (TGFβ), platelet growth factor (PDGF) signalling and Reactive Oxygen Species (ROS) production govern and regulate cancer-stem cell biology. In this work, we focus on the role of the NADPH oxidase 4 (NOX4) downstream of TGFβ signalling in the GSCs. NOX4 utilises NADPH to generate ROS; TGFβ induces NOX4 expression, thus increasing ROS production.Interestingly, NOX4 itself regulates GSC self-renewal and modulates Since TGFβ regulates PDGFB in GSC, we analysed how PDGFB modulates NOX4 expression and increases ROS production. Both TGFβ and PDGF signalling regulate GSC proliferation in a NOX4/ROS-dependent manner. The transcription factor NRF2, involved in the transcriptional regulation of antioxidant and metabolic responses, is regulated by both TGFβ and NOX4. This results in an antioxidant response, which positively contributes to GSC self-renewal and proliferation. In conclusion, this work functionally establishes NOX4 as a key mediator of GSC biology.

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“…Moreover, mouse models of certain liver diseases, such as those induced by HCV infection or NASH are poor surrogates since they fail to replicate the chronicity observed in humans (22). Routine immunohistochemical (IHC) staining of human liver biopsies can identify macrophages in formalin-fixed paraffin-embedded (FFPE) tissues; however, there are many limitations, including the inability to stain multiple antigens on the same cellular compartment (23), and depend on the availability of primary antibodies raised in different species to prevent cross-reactivity (21).…”

Section: Introductionmentioning

confidence: 99%

Multispectral Imaging Differentiates Unique Macrophage Profiles in Patients with Distinct Chronic Liver Diseases

Saldarriaga

Booth

Freiberg

et al. 2019

Preprint

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List of Abbreviations:AIH: autoimmune hepatitis FFPE: formalin-fixed, paraffin-embedded H&E: Hematoxylin and eosin 2 HCV: hepatitis C virus IHC: immunohistochemical LSEC: liver sinusoidal endothelial cells MHAI: Modified hepatitis activity index NASH: nonalcoholic steatohepatitis PASD: Periodic acid-Schiff with diastase ROI: regions of interest TSA: tyramide signal amplification t-SNE: t-distributed stochastic neighbor embedding ABSTRACT Intrahepatic macrophages influence the composition of the microenvironment, host immune response to liver injury, and development of fibrosis. Compared to stellate cells, the role of intrahepatic macrophages in the development of fibrosis remains ill defined. Multispectral imaging allows detection of multiple markers in situ in human formalin-fixed, paraffin-embedded tissue. This cutting-edge technology is ideal for analyzing human liver tissues since it allows spectral unmixing of fluorophore signals, subtraction of auto-fluorescence, and preserves architecture and the in vivo hepatic milieu.We analyzed resident Kupffer cells (CD68+), monocyte-derived macrophages (Mac387+), profibrogenic macrophages (CD163+), and co-expression of pro-inflammatory (CD14) and antiinflammatory (CD16) markers in liver biopsies from patients with hepatitis C virus (HCV) and different stages of fibrosis. Liver biopsies with advanced fibrosis showed increased accumulation of CD163+, MAC387+ and CD68+ macrophages in the portal tracts when compared to those with minimal fibrosis.Imaging software generated t-distributed stochastic neighbor embedding (t-SNE) plots and phenotype matrices that facilitated comparison of macrophage profiles. These included monocyte-derived (CD68+/Mac387+) and pro-fibrotic/anti-inflammatory (CD163+/CD16+) phenotypes. We established that the utility of this platform could be extended to liver biopsies from patients with other chronic liver diseases including nonalcoholic steatohepatitis and autoimmune hepatitis. Each disease exhibited a unique profile after spectral imaging analysis and this platform holds the potential to identify patients predisposed to progressive liver disease based on the macrophage composition. In summary, spectral imaging is a powerful tool that enables analysis of macrophage profiles in different types of chronic liver diseases and has potential to change the manner in which we evaluate liver biopsies leading to more personalized treatment strategies.

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Multispectral imaging for quantitative and compartment‐specific immune infiltrates reveals distinct immune profiles that classify lung cancer patients

Cited by 155 publications

References 61 publications

Cancer stemness, intratumoral heterogeneity, and immune response across cancers

Cancer stemness, intratumoral heterogeneity, and immune response across cancers

NOX4 regulates TGFβ-induced proliferation and self-renewal in glioblastoma stem cells

Multispectral Imaging Differentiates Unique Macrophage Profiles in Patients with Distinct Chronic Liver Diseases

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