Microenvironmental Th9 and Th17 lymphocytes induce metastatic spreading in lung cancer

Journal of Clinical Investigation, Journal Year: 2020, Volume and Issue: 130(7), P. 3560 - 3575

Published: March 31, 2020

Immune microenvironment plays a critical role in lung cancer control versus progression and metastasis. In this investigation, we explored the effect of tumor-infiltrating lymphocyte subpopulations on biology by studying vitro cocultures, vivo mouse models, human tissue. Lymphocyte conditioned media (CM) induced epithelial-mesenchymal transition (EMT) migration both primary cells cell lines. Correspondingly, major accumulation Th9 Th17 was detected tissue correlated with poor survival. Coculturing Th9/Th17 or exposing them to respective CM EMT modulated expression profile genes implicated These features were reproduced signatory cytokines IL-9 IL-17, gene regulatory profiles evoked these partly overlapping complementary. Coinjection tumor WT, Rag1-/-, Il9r-/-, Il17ra-/- mice altered growth Accordingly, inhibition IL-17 neutralizing antibodies decreased slowed conclusion, lymphocytes induce EMT, thereby promoting metastatic spreading offering potentially novel therapeutic strategies.

Language: Английский

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Hyperspectral and multispectral imaging in digital and computational pathology: a systematic review [Invited]

Biomedical Optics Express, Journal Year: 2020, Volume and Issue: 11(6), P. 3195 - 3195

Published: May 8, 2020

Hyperspectral imaging (HSI) and multispectral (MSI) technologies have the potential to transform fields of digital computational pathology. Traditional digitized histopathological slides are imaged with RGB imaging. Utilizing HSI/MSI, spectral information across wavelengths within beyond visual range can complement spatial for creation computer-aided diagnostic tools both stained unstained histological specimens. In this systematic review, we summarize methods uses HSI/MSI staining color correction, immunohistochemistry, autofluorescence, research. Studies include hematology, breast cancer, head neck skin diseases central nervous, gastrointestinal, genitourinary systems. The use suggest an improvement in detection clinical practice compared traditional analysis, brings new opportunities analysis samples, such as or alleviating inter-laboratory variability samples. Nevertheless, number studies field is currently limited, more research needed confirm advantages technology conventional imagery.

Language: Английский

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Precision immunoprofiling by image analysis and artificial intelligence

Virchows Archiv, Journal Year: 2018, Volume and Issue: 474(4), P. 511 - 522

Published: Nov. 23, 2018

Clinical success of immunotherapy is driving the need for new prognostic and predictive assays to inform patient selection stratification. This requirement can be met by a combination computational pathology artificial intelligence. Here, we critically assess approaches supporting development standardized methodology in assessment immune-oncology biomarkers, such as PD-L1 immune cell infiltrates. We examine immunoprofiling through spatial analysis tumor-immune interactions multiplexing technologies predictor response cancer treatment. Further, discuss how integrated bioinformatics enable amalgamation complex morphological phenotypes with multiomics datasets that drive precision medicine. provide an outline machine learning (ML) intelligence tools illustrate fields application immune-oncology, pattern-recognition large deep survival analysis. Synergies surgical analyses are expected improve stratification immuno-oncology. propose future clinical demands will best (1) dedicated research at interface bioinformatics, supported professional societies, (2) integration data sciences digital image education pathologists.

Language: Английский

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The Prognostic Importance of CD20+ B lymphocytes in Colorectal Cancer and the Relation to Other Immune Cell subsets

Scientific Reports, Journal Year: 2019, Volume and Issue: 9(1)

Published: Dec. 27, 2019

Abstract The anti-tumour immune response is critical to patient prognosis in colorectal cancer (CRC). aim of this study was investigate infiltration B lymphocytes into CRC tumours, and their clinical relevance, prognostic value relation other cell subsets. We used multiplexed immunohistochemistry multispectral imaging assay the amount infiltrating CD20 + along with CD8 cytotoxic T cells, FOXP3 regulatory CD68 macrophages CD66b neutrophils, 316 archival tissue specimens. A higher density associated tumours right colon ( P = 0.025) lower stages 0.009). Furthermore, patients whose were highly infiltrated by had a significantly improved disease-specific survival (HR 0.45, 95% CI 0.28–0.73, 0.001), which remained significant multivariable analysis. positively < part role found be cooperative effect between these lymphocyte Our results support favourable tumour-infiltrating CRC. suggested.

Language: Английский

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LncRNA PKMYT1AR promotes cancer stem cell maintenance in non-small cell lung cancer via activating Wnt signaling pathway

Molecular Cancer, Journal Year: 2021, Volume and Issue: 20(1)

Published: Dec. 1, 2021

Non-small cell lung cancer (NSCLC) is the most common type of human cancers, which has diverse pathological features. Although many signaling pathways and therapeutic targets have been defined to play important roles in NSCLC, limiting efficacies achieved.Bioinformatics methods were used identify differential long non-coding RNA expression NSCLC. Real-time RT-PCR experiments examine pattern lncRNA PKMYT1AR, miR-485-5p. Both vitro vivo functional assays performed investigate role PKMYT1AR/miR-485-5p/PKMYT1 axis on regulating proliferation, migration tumor growth. Dual luciferase reporter assay, fluorescent situ hybridization (FISH), immunoblot, co-immunoprecipitation verify molecular mechanism.Here, we a human-specific (lncRNA, ENST00000595422), termed PKMYT1AR (PKMYT1 associated lncRNA), that induced NSCLC by Yin Yang 1 (YY1) factor, especially cancerous lines (H358, H1975, H1299, H1650, A549 SPC-A1) compared normal bronchial epithelium line (BEAS-2B). We show high correlates with worse clinical outcome, knockdown inhibits xenograft formation abilities. Bioinformatic analysis assay demonstrate directly interacts miR-485-5p attenuate inhibitory its downstream oncogenic factor PKMYT1 (the protein kinase, membrane-associated tyrosine/threonine 1) Furthermore, uncover downregulated both peripheral blood serum isolated from patients reciprocal control groups. Consistently, forced proliferation abilities cells. Moreover, provide evidence showing targeting antisense oligonucleotide (ASO) dramatically inhibit growth vivo. Mechanistic study shows PKMYT1AR/ /PKMYT1 promotes stem cells (CSCs) maintenance via inhibiting β-TrCP1 mediated ubiquitin degradation β-catenin proteins, turn causes enhanced tumorigenesis.Our findings reveal critical PKMYT1AR/miR-485-5p during progression, could be as novel future.

Language: Английский

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Multiplexed Immunohistochemistry for Molecular and Immune Profiling in Lung Cancer—Just About Ready for Prime-Time?

Cancers, Journal Year: 2019, Volume and Issue: 11(3), P. 283 - 283

Published: Feb. 27, 2019

As targeted molecular therapies and immuno-oncology have become pivotal in the management of patients with lung cancer, essential requirement for high throughput analyses clinical validation biomarkers has even more intense, response rates maintained 20%–30% range. Moreover, list treatment alternatives, including combination therapies, is rapidly evolving. The profiling specific tumor-associated immune contexture may be predictive or resistance to these therapeutic strategies. Multiplexed immunohistochemistry an effective proficient approach simultaneously identify proteins abnormalities, determine spatial distribution activation state cells, as well presence immunoactive expression. This method highly advantageous investigating evasion mechanisms discovering potential assess action predict a given treatment. review provides views on current technological status evidence applications multiplexing how it could applied optimize cancer.

Language: Английский

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Nongenetic Evolution Drives Lung Adenocarcinoma Spatial Heterogeneity and Progression

Cancer Discovery, Journal Year: 2021, Volume and Issue: 11(6), P. 1490 - 1507

Published: Feb. 9, 2021

Abstract Cancer evolution determines molecular and morphologic intratumor heterogeneity challenges the design of effective treatments. In lung adenocarcinoma, disease progression prognosis are associated with appearance morphologically diverse tumor regions, termed histologic patterns. However, link between features remains elusive. Here, we generated multiomics spatially resolved profiles patterns from primary which integrated data &gt;2,000 patients. The transition indolent to aggressive was not driven by genetic alterations but epigenetic transcriptional reprogramming reshaping cancer cell identity. A signature quantifying this an independent predictor patient in multiple human cohorts. Within individual tumors, highly multiplexed protein spatial profiling revealed coexistence immune desert, inflamed, excluded matched pattern composition. Our results provide a detailed map adenocarcinoma heterogeneity, tracing nongenetic routes evolution. Significance: Lung adenocarcinomas classified based on prevalence. tumors exhibit unknown features. We characterized mechanisms underlying markers predicting prognosis. Intratumor determined microenvironments, warranting their study context current immunotherapies. This article is highlighted Issue feature, p. 1307

Language: Английский

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The Cancer Immunotherapy Biomarker Testing Landscape

Archives of Pathology & Laboratory Medicine, Journal Year: 2019, Volume and Issue: 144(6), P. 706 - 724

Published: Nov. 12, 2019

Context.— Cancer immunotherapy provides unprecedented rates of durable clinical benefit to late-stage cancer patients across many tumor types, but there remains a critical need for biomarkers accurately predict response. Although some tests are associated with approved therapies and considered validated, other still emerging at various states translational exploration. Objective.— To provide pathologists current practical update on the evolving field testing. The scientific background, data, testing methodology following reviewed: programmed death ligand-1 (PD-L1), mismatch repair, microsatellite instability, mutational burden, polymerase δ ɛ mutations, neoantigens, tumor-infiltrating lymphocytes, transcriptional signatures immune responsiveness, resistance biomarkers, microbiome. Data Sources.— Selected publications trial data representing immunotherapy. Conclusions.— field, including use biomarker patient response, is in evolution. PD-L1, instability helping guide US Food Drug Administration–approved therapies, better predictors response resistance. Several categories characteristics underlying responsiveness may represent next generation predictive biomarkers. Pathologists have important roles responsibilities as continues develop, leadership studies, exploration novel accurate timely implementation newly validated companion diagnostics.

Language: Английский

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Association between programmed death-ligand 1 expression, immune microenvironments, and clinical outcomes in epidermal growth factor receptor mutant lung adenocarcinoma patients treated with tyrosine kinase inhibitors

European Journal of Cancer, Journal Year: 2019, Volume and Issue: 124, P. 110 - 122

Published: Nov. 21, 2019

Language: Английский

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An immune score reflecting pro- and anti-tumoural balance of tumour microenvironment has major prognostic impact and predicts immunotherapy response in solid cancers

EBioMedicine, Journal Year: 2023, Volume and Issue: 88, P. 104452 - 104452

Published: Jan. 30, 2023

Cancer immunity is based on the interaction of a multitude cells in spatial context tumour tissue. Clinically relevant immune signatures are therefore anticipated to fundamentally improve accuracy predicting disease progression.Through multiplex situ analysis we evaluated 15 cell classes 1481 samples. Single-cell and bulk RNAseq data sets were used for functional validation prognostic predictive associations.By combining information anti-tumoural CD8+ lymphocytes supportive CD68+CD163+ macrophages colorectal cancer generated signature activation (SIA). The impact SIA was independent conventional parameters comparable with state-of-art score. also associated patient survival oesophageal adenocarcinoma, bladder cancer, lung adenocarcinoma melanoma, but not endometrial, ovarian squamous carcinoma. We identified as major producers complement C1q, which could serve surrogate marker this macrophage subset. Consequently, RNA-based version (ratio CD8A C1QA) from these six types. Finally, CD8A/C1QA mRNA ratio response checkpoint inhibitor therapy.Our findings extend current concepts procure microenvironment provide an high clinical potential common human types.Swedish Society, Lions Foundation, Selanders P.O. Zetterling U-CAN supported by SRA CancerUU, Uppsala University Region Uppsala.

Language: Английский

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