Robust enumeration of cell subsets from tissue expression profiles

Newman, Aaron M.; Liu, Chih Long; Green, Michael R.; Gentles, Andrew J.; Feng, Weiguo; Xu, Yue; Hoang, Chuong D.; Diehn, Maximilian; Alizadeh, Ash A.

doi:10.1038/nmeth.3337

Cited by 9,742 publications

(9,602 citation statements)

References 30 publications

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“…25 We profiled the relative enrichment of 22 immune cell types across FID, WID and PID in TCGA TMB-Lo and TMB-Hi tumors (Figure 2). Irrespective of TMB, the majority of immune cell types showed differential enrichment between FID and PID subclasses.…”

Section: Resultsmentioning

confidence: 99%

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Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

et al. 2018

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Mounting evidence supports a role for the immune system in breast cancer outcomes. The ability to distinguish highly immunogenic tumors susceptible to anti-tumor immunity from weakly immunogenic or inherently immune-resistant tumors would guide development of therapeutic strategies in breast cancer. Genomic, transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohorts were used to examine statistical associations between tumor mutational burden (TMB) and the survival of patients whose tumors were assigned to previously-described prognostic immune subclasses reflecting favorable, weak or poor immune-infiltrate dispositions (FID, WID or PID, respectively). Tumor immune subclasses were associated with survival in patients with high TMB (TMB-Hi, P < 0.001) but not in those with low TMB (TMB-Lo, P = 0.44). This statistical relationship was confirmed in the METABRIC cohort (TMB-Hi, P = 0.047; TMB-Lo, P = 0.39), and also found to hold true in the more-indolent Luminal A tumor subtype (TMB-Hi, P = 0.011; TMB-Lo, P = 0.91). In TMB-Hi tumors, the FID subclass was associated with prolonged survival independent of tumor stage, molecular subtype, age and treatment. Copy number analysis revealed the reproducible, preferential amplification of chromosome 1q immune-regulatory genes in the PID immune subclass. These findings demonstrate a previously unappreciated role for TMB as a determinant of immune-mediated survival of breast cancer patients and identify candidate immune-regulatory mechanisms associated with immunologically cold tumors. Immune subtyping of breast cancers may offer opportunities for therapeutic stratification.

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Section: Resultsmentioning

confidence: 99%

“…The gene signature matrix of 22 immune cell types (LM-22) developed by Alizadeh and colleagues 25 was used as input for the Gene Set Variation Analysis (GSVA) algorithm of Hanzelmann and colleagues. 58 GSVA was implemented by R package “GSVA”.…”

Section: Methodsmentioning

confidence: 99%

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

et al. 2018

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“…Genes significantly up-modulated in human M1 and in M2-polarized macrophages, 42 respectively and genes of the LM22 Cibersort list 43 were analyzed as M1 and M2 gene patterns (Supplementary Table S3) in the GHEA dataset by ssGSEA, as described. 44 ERS score was calculated as described. 11 CCL2 expression was analyzed in silico in the GSE70360 public dataset 14 with processed data retrieved from the GEO repository.…”

Section: Methodsmentioning

confidence: 99%

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

et al. 2018

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Through whole-transcriptome profiling of HER2+ breast carcinomas (BCs), we previously showed that those sensitive to trastuzumab are addicted to this oncoprotein and are enriched in immune pathways, raising the hypothesis that HER2 itself regulates immune cell recruitment. In the present study we investigated the relationship between HER2 activity and the pro-trastuzumab tumor immune milieu. Gene expression profiling and immunohistochemistry analysis of 53 HER2+ BCs showed that trastuzumab-sensitive tumors expressed significantly higher levels of chemokines involved in immune cell recruitment, with higher infiltration of T cells and monocytes, and higher levels of PD-1 ligands than tumors that do not benefit from trastuzumab. In vitro analysis in HER2+ BC cells revealed that CCL2 production was induced by HER2 stimulation with EGF/HRG via the PI3K-NF-kB axis, and down-modulated by HER2 inhibition with trastuzumab. CCL2 expression was higher in HER2+/ER− than HER2+/ER+ BC cell lines, and degradation of ER by fulvestrant induced an enhancement in NF-κB transcriptional activity and consequent CCL2 expression. Trastuzumab efficacy relied on CCL2 levels and monocytes present in the tumor microenvironment in FVB mice bearing HER2+ mammary carcinoma cells. HER2 signals were also found to sustain the expression of PD-1 ligands in tumor cells via the MEK pathway.Overall, our results support the concept that the activated HER2 oncogene regulates recruitment and activation of tumor infiltrating immune cells and trastuzumab activity by inducing CCL2 and PD-1 ligands and that ER activity negatively controls the HER2-driven pro-trastuzumab tumor microenvironment.

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“…To link the signatures of VAT and spleen tissue macrophages to signatures derived from in vitro activated macrophages, the list of present genes of dataset I were used as input for CIBERSORT 40 . As signature matrix, 29 macrophage subsets including inactivated human macrophages were used 41 .…”

Section: Bioinformaticsmentioning

confidence: 99%

Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

Camell

Sander

Spadaro

et al. 2017

Nature

369

352

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Catecholamine-induced lipolysis, the first step in generation of energy substrates through hydrolysis of triglycerides (TGs) 1, declines with age 2,3. The defect in mobilization of free fatty acids (FFA) in elderly is accompanied with increased visceral adiposity, lower exercise capacity, failure to maintain core body temperature during cold stress, and reduced ability to survive starvation. While catecholamine signaling in adipocytes is normal in elderly, how lipolysis is impaired in aging remains unknown 2,4. Here we uncover that the adipose tissue macrophages (ATMs) regulate age-related reduction in adipocyte lipolysis by lowering the bioavailability of norepinephrine (NE). Unexpectedly, unbiased whole transcriptome analyses of adipose macrophages revealed that aging upregulates genes controlling catecholamine degradation in an NLRP3 inflammasome-dependent manner. Deletion of NLRP3 in aging restored catecholamine-induced lipolysis through downregulation of growth differentiation factor-3 (GDF3) and monoamine oxidase-a (MAOA) that is known to degrade NE. Consistent with this, deletion of GDF3 in inflammasome-activated macrophages improved lipolysis by decreasing MAOA and caspase-1. Furthermore, inhibition of MAOA reversed age-related reduction in adipose tissue NE concentration and restored lipolysis with increased levels of key lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Our study reveals that targeting neuro-innate signaling between sympathetic nervous system and macrophages may offer new approaches to mitigate chronic inflammation-induced metabolic impairment and functional decline.

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Robust enumeration of cell subsets from tissue expression profiles

Cited by 9,742 publications

References 30 publications

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

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