Deconvolving clinically relevant cellular immune crosstalk from bulk gene expression using CODEFACS and LIRICS

Wang, K; Patkar, Sushant; Js, Lee; Gertz, EM; Robinson, Welles; Ruppin, Eytan; Dr, Crawford; Aa, Schäffer; Ruppin, Eytan

doi:10.1101/2021.01.20.427515

Cited by 4 publications

(4 citation statements)

References 76 publications

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“…It is reported that the exhaustive molecular marker, PD-1, which is expressed on the surface of exhausted T cells, impaired the tumor-killing effects in tumor tissues [26,27]. Therefore, the immune checkpoint blocker PD-1 mAb is the most widely used reagent for anti-tumor immunotherapy in clinical practice [28][29][30]. However, prior to performing the PD-1 mAb therapy, positive detection of PD-1 is necessary [31,32].…”

Section: Discussionmentioning

confidence: 99%

NGF-NGFR communication inefficiency induces T Cell exhaustion impairing PD-1 immunotherapy in hepatocellular carcinoma

Yang

et al. 2023

Preprint

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The number of T cells that infiltrate tumor tissues in hepatocellular carcinoma (HCC) is significantly low. The molecular mechanism underlying T cell proliferation in tumor tissues is poorly understood. The present study revealed that during the process of T cell infiltration from adjacent tissues to tumor tissues, the NGF-NGFR communication inefficiency occurred in the tumor tissues of HCC patients. Importantly, the tumor cell-secreted NGF interacted with NGFR on the membranes of the infiltrated T cells, which promoted proliferation of these cells through mitotic spindle signal activation. Mechanistically, the mitotic spindle signal activation promoted the proliferation was mediated by the HDAC1 unclear trans-localization-inhibited PREX1 expression. Further, PD-1 mAb acted synergistically with the NGF-NGFR communication to suppress tumor progression in both mouse model and HCC patients. In addition, NGF–NGFR communication was positively correlated with the PD-1/PDL-1 expression. However, NGF and NGFR expressions were low in tumor tissues, which was responsible for the incursive clinicopathological features and the disappointing prognosis in HCC patients. Collectively, the results suggested that NGF-NGFR communication inefficiency impaired PD-1 mAb immunotherapy and could, therefore, be utilized as a novel therapeutic target in the treatment of HCC patients in clinical practice.

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Section: Discussionmentioning

confidence: 99%

NGF-NGFR communication inefficiency induces T Cell exhaustion impairing PD-1 immunotherapy in hepatocellular carcinoma

Yang

et al. 2023

Preprint

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“…Importantly, conducting cell abundance deconvolution prior to cell-cell interaction scoring can help normalize heterogeneous samples and hence measure genuine changes in cell-cell interaction instead of those driven by a shift in cell composition. Similar approaches have been used in bulk expression studies, 34 but, here again, the availability of single-cell RNA-seq could alleviate the need for such computational tricks and directly measure LR interaction from pure populations of cells as conducted by multiple methods recently published. [35][36][37] As mentioned above, however, single-cell gene expression data is not available for pure DCIS specimens, and approaches like ours are needed to overcome the resulting lack of data.…”

Section: Discussionmentioning

confidence: 99%

Differential Analysis of Stromal-Epithelial Interactions between In Situ and Invasive Breast Cancer using Gene Expression Profiling

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Dempsey

Murrow

et al. 2022

Preprint

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Background: Changes in microenvironment cell-cell interactions (CCI) during the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) are poorly understood. Gene expression studies are confounded by cellular heterogeneity and few separate stromal and epithelial contributions, resulting in a lack of reliable prognostic biomarker to guide treatment decisions. Methods: The gene expression of 293 microdissected regions from DCIS (92 epithelial, 31 stromal) and IDC (78 epithelial, 30 stromal) cases was aggregated from 6 datasets. Expression signatures of 6 cell lineages extracted from normal breast single-cell profiling were used to correct for differences in cell abundance. Subtype-specific functional differences between DCIS and IDC were measured for each region type using Gene Set Enrichment Analysis (GSEA). DCIS-IDC stromal-epithelial interactions were compared using the expression product of 139 ligand-receptor (LR) pairs permuting the DCIS-IDC labels to assess significance. Results: Variation in cell-lineage abundance separated epithelial regions into 4 clusters, including one enriched for DCIS (Myoepi-Enriched) and two for IDC (Infiltrated, Vascularized). GSEA on cell lineage normalized expression data identified subtype-independent changes in epithelial regions (induction of Extracellular Matrix maintenance genes, reduction of Tp53 signaling in IDC), as well as subtype-specific changes (proliferation in ER- and Her2- IDC, reduction in Nucleotide Excision Repair in ER+ IDC). In the stroma, Notch and Rho-GTPase signaling were induced in IDC irrespective of subtype. The stromal-epithelial interaction level of 6 and 4 LR pairs were significantly enriched in DCIS and IDC, respectively. Five of the 6 DCIS-enriched LR pairs involved ephrin interactions, with interaction level progressively decreasing from normal to DCIS to IDC. In contrast, 2 IDC-enriched LR pairs involved T-cell activity likely regulating Treg proliferation (CD28-CD86) or T and NK cells stimulation (CD226-PVR). Notably, the bulk expression product of one identified LR pair (EPHB4-EFNB1) was associated with poor survival in IDC (HR=1.47, p=0.04) suggesting that early remodeling of this stromal-epithelial interaction may have long-lasting impact on disease severity. Conclusions: The observed changes in cell states and stromal-epithelial interactions, beyond those driven by difference in cell abundance, may lead to new biomarkers for prognosis and targets for secondary prevention.

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“…Second, using a precomputed estimates of cell abundance or cell-type-specific signature based on deconvolving cell-type-specific gene expression in each sample from bulk expression 44 of LUAD patients, patients with higher average expression of the unique signature (65 genes) identified in Siah1a/2 ablated macrophages were also found to have increased myeloid cells (CD14 + ) infiltration (Figure 7G). The TCGA dataset of the LUAD was also used to identify which of the 65 genes are associated with worse survival.…”

Section: Siah1a/2 Deletion In Macrophages Promotes a Pro-fibrotic Phe...mentioning

confidence: 99%

Control of alveolar macrophage differentiation by Siah1a/2 ubiquitin ligases limits carcinogen-induced lung adenocarcinoma

Scortegagna

Bradley

et al. 2022

Preprint

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Tumor microenvironment components, including T and myeloid cells, play important roles in lung adenocarcinoma (LADC) progression and response to therapy. Here, we identify a role for Siah1a/2 ubiquitin ligases in controlling alveolar macrophage (AM) differentiation and urethane-induced LADC. Genetic ablation of Siah1a/2 in AMs enriched their immature state, coinciding with increased pro-tumorigenic and inflammatory gene signatures and abundance of Siah1a/2 substrates NRF2 and β-catenin. Urethane administration to mice enriched the population of monocytic and immature-like AMs, which were more prevalent in the lungs of mice carrying Siah1a/2-ablated macrophages. While resembling transitional profibrotic macrophages often seen in lung fibrosis, enrichment of immature AMs coincided with the development of more frequent and larger lung tumors in urethane-treated mice harboring Siah1a/2 ablated macrophages compared with controls. Gene expression signature of Siah1a/2 ablated immature-like AMs is associated with increased infiltration of CD14+ immune cells and worse survival of LADC patients. Our findings identify Siah1a/2 as gatekeepers of cancer development by controlling AM differentiation and profibrotic phenotypes contributing to carcinogen-induced lung cancer.

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Deconvolving clinically relevant cellular immune crosstalk from bulk gene expression using CODEFACS and LIRICS

Cited by 4 publications

References 76 publications

NGF-NGFR communication inefficiency induces T Cell exhaustion impairing PD-1 immunotherapy in hepatocellular carcinoma

NGF-NGFR communication inefficiency induces T Cell exhaustion impairing PD-1 immunotherapy in hepatocellular carcinoma

Differential Analysis of Stromal-Epithelial Interactions between In Situ and Invasive Breast Cancer using Gene Expression Profiling

Control of alveolar macrophage differentiation by Siah1a/2 ubiquitin ligases limits carcinogen-induced lung adenocarcinoma

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