Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression

Becht, Étienne; Giraldo, Nicolás A.; Lacroix, Laetitia; Buttard, Bénédicte; Elarouci, Nabila; Petitprez, Florent; Sèlves, Janick; Laurent‐Puig, Pierre; Sautès-Fridman, Catheriné; Fridman, Wolf H.; Reyniès, Aurélien de

doi:10.1186/s13059-016-1070-5

Cited by 2,472 publications

(2,320 citation statements)

References 27 publications

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“…As the main biological difference between the two subtypes lied in the tumor microenvironment, we used the MCPcounter R package 27 to deconvoluate the immune infiltrate and compute a score of the absolute abundance of eight immune and two stromal cell populations. When compared to the classical subtype, the immunological subtype had higher score of T-cells ( P < 0.0001), cytotoxic lymphocytes ( P < 0.0001), B lineage ( P = 0.0025), monocytic lineage ( P < 0.0001) and myeloid dendritic cells ( P < 0.0001) (Supplementary Table S1).…”

Section: Resultsmentioning

confidence: 99%

“…The Microenvironment Cell Populations-counter (MCP-counter) R package 27 was used for deconvolution of the immune infiltrate in each OPL sample. This method allows computing a score of the absolute abundance of eight immune cell types (T-cells; CD8 T-cells; Cytotoxic lymphocytes; NK cells; B lineage; Monocytic lineage; Myeloid dendritic cells; and Neutrophils) as well as of two stromal cell populations (endothelial cells and fibroblasts) in heterogeneous tissues from transcriptomic data.…”

Section: Methodsmentioning

confidence: 99%

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Immunological and classical subtypes of oral premalignant lesions

et al. 2018

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Oral squamous cell carcinoma (OSCC) is a major cause of cancer-associated morbidity and mortality and may develop from oral premalignant lesions (OPL). An improved molecular classification of OPL may help refining prevention strategies. We identified two main OPL gene-expression subtypes, named immunological and classical, in 86 OPL (discovery dataset). A gene expression-based score was then developed to classify OPL samples from three independent datasets, including 17 (GSE30784),13 (GSE10174) and 15 (GSE85195) OPLs, into either one of the two gene-expression subtypes. Using the single sample gene set enrichment analysis, enrichment scores for immune-related pathways were different between the two OPL subtypes. In OPL from the discovery set, loss of heterozygosities (LOH) at 3p14, 17p13, TP53, 9p21 and 8p22 and miRNA gene expression profiles were analyzed. Deconvolution of the immune infiltrate was performed using the Microenvironment Cell Populations-counter tool. A multivariate analysis revealed that decreased miRNA-142-5p expression (P = 0.0484) and lower T-cell, monocytic and myeloid dendritic cells (MDC) immune infiltration (T-cells, P = 0.0196; CD8 T cells, P = 0.0129; MDC, P = 0.0481; and monocytes, P = 0.0212) were associated with oral cancer development in the immunological subtype only. In contrast, LOH at 3p14 (P = 0.0241), 17p13 (P = 0.0348) and TP53 (P = 0.004) were associated with oral cancer development in the classical subtype only. In conclusion, we identified 2 subtypes of OPLs, namely immune and classical, which may benefit from different and specific personalized prevention interventions.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Immunological and classical subtypes of oral premalignant lesions

et al. 2018

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“…The total number of tumors analyzed in this study amounts to 5953 (Table 1). We first examined the expression variability of each of the metagenes relevant to tumor-infiltrating immune cell types (determined by using the MCP counter method) 27,30 and mRNAs encoding annexins (ANXA), chemokines (CCL, CXCL, XCL), chemokine receptors (CCR, CXCR, XCR, CCRL), formyl peptide receptors (FPR), purinergic receptors (ADOR, P2RX, P2RY), compared to housekeeping genes (ACTB, GADPH, TUB), as this is typically done when protein expression is measured by immunoblot analysis. However the variability in the expression of housekeeping genes was not expected to be smaller than that of the genes of interest (including immune metagenes) due to the normalization methods of microarrays.…”

Section: Resultsmentioning

confidence: 99%

“…We use data that were already normalized, as provided from the different repository websites. The MCPcounter 27 R-package was used for estimating immune cell type activities. This method uses groups of genes to construct metagenes, whose expressions measure indirectly immune cell abundances.…”

Section: Methodsmentioning

confidence: 99%

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Impact of chemotactic factors and receptors on the cancer immune infiltrate: a bioinformatics study revealing homogeneity and heterogeneity among patient cohorts

et al. 2018

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Multiple soluble factors including proteins (in particular chemokines), non-proteinaceous factors released by dead cells, as well as receptors for such factors (in particular chemokine receptors, formyl peptide receptors and purinergic receptors), influence the recruitment of distinct cell subsets into the tumor microenvironment. We performed an extensive bioinformatic analysis on tumor specimens from 5953 cancer patients to correlate the mRNA expression levels of chemotactic factors/receptors with the density of immune cell types infiltrating the malignant lesions. This meta-analysis, which included specimens from breast, colorectal, lung, ovary and head and neck carcinomas as well as melanomas, revealed that a subset of chemotactic factors/receptors exhibited a positive and reproducible correlation with several infiltrating cell types across various solid cancers, revealing a universal pattern of association. Hence, this meta-analysis distinguishes between homogeneous associations that occur across different cancer types and heterogeneous correlations, that are specific of one organ. Importantly, in four out of five breast cancer cohorts for which clinical data were available, the levels of expression of chemotactic factors/receptors that exhibited universal (rather than organ-specific) positive correlations with the immune infiltrate had a positive impact on the response to neoadjuvant chemotherapy. These results support the notion that general (rather than organ-specific) rules governing the recruitment of immune cells into the tumor bed are particularly important in determining local immunosurveillance and response to therapy.

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Transcriptomic Analyses of Pretreatment Tumor Biopsy Samples, Response to Neoadjuvant Chemoradiotherapy, and Survival in Patients With Advanced Rectal Cancer

et al. 2023

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ImportanceNeoadjuvant chemoradiotherapy (CRT) is the standard of care for advanced rectal cancer. Yet, estimating response to CRT remains an unmet clinical challenge.ObjectiveTo investigate and better understand the transcriptomic factors associated with response to neoadjuvant CRT and survival in patients with advanced rectal cancer.Design, Setting, and ParticipantsA single-center, retrospective, case series was conducted at a comprehensive cancer center. Pretreatment biopsies from 298 patients with rectal cancer who were later treated with neoadjuvant CRT between April 1, 2004, and September 30, 2020, were analyzed by RNA sequencing. Data analysis was performed from July 1, 2021, to May 31, 2022.ExposuresChemoradiotherapy followed by total mesorectal excision or watch-and-wait management.Main Outcomes and MeasuresTranscriptional subtyping was performed by consensus molecular subtype (CMS) classification. Immune cell infiltration was assessed using microenvironment cell populations-counter (MCP-counter) scores and single-sample gene set enrichment analysis (ssGSEA). Patients with surgical specimens of tumor regression grade 3 to 4 or whose care was managed by the watch-and-wait approach for more than 3 years were defined as good responders.ResultsOf the 298 patients in the study, 205 patients (68.8%) were men, and the median age was 61 (IQR, 52-67) years. Patients classified as CMS1 (6.4%) had a significantly higher rate of good response, albeit survival was comparable among the 4 subtypes. Good responders exhibited an enrichment in various immune-related pathways, as determined by ssGSEA. Microenvironment cell populations-counter scores for cytotoxic lymphocytes were significantly higher for good responders than nonresponders (median, 0.76 [IQR, 0.53-1.01] vs 0.58 [IQR, 0.43-0.83]; P &lt; .001). Cytotoxic lymphocyte MCP-counter score was independently associated with response to CRT, as determined in the multivariable analysis (odds ratio, 3.81; 95% CI, 1.82-7.97; P &lt; .001). Multivariable Cox proportional hazards regression analysis, including postoperative pathologic factors, revealed the cytotoxic lymphocyte MCP-counter score to be independently associated with recurrence-free survival (hazard ratio [HR], 0.38; 95% CI, 0.16-0.92; P = .03) and overall survival (HR, 0.16; 95% CI, 0.03-0.83; P = .03).Conclusions and RelevanceIn this case series of patients with rectal cancer treated with neoadjuvant CRT, the cytotoxic lymphocyte score in pretreatment biopsy samples, as computed by RNA sequencing, was associated with response to CRT and survival. This finding suggests that the cytotoxic lymphocyte score might serve as a biomarker in personalized multimodal rectal cancer treatment.

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Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression

Cited by 2,472 publications

References 27 publications

Immunological and classical subtypes of oral premalignant lesions

Immunological and classical subtypes of oral premalignant lesions

Impact of chemotactic factors and receptors on the cancer immune infiltrate: a bioinformatics study revealing homogeneity and heterogeneity among patient cohorts

Transcriptomic Analyses of Pretreatment Tumor Biopsy Samples, Response to Neoadjuvant Chemoradiotherapy, and Survival in Patients With Advanced Rectal Cancer

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