Simultaneous enumeration of cancer and immune cell types from bulk tumor gene expression data
- University of Lausanne, Switzerland
- Lausanne University Hospital, Switzerland
Abstract
Immune cells infiltrating tumors can have important impact on tumor progression and response to therapy. We present an efficient algorithm to simultaneously estimate the fraction of cancer and immune cell types from bulk tumor gene expression data. Our method integrates novel gene expression profiles from each major non-malignant cell type found in tumors, renormalization based on cell-type specific mRNA content, and the ability to consider uncharacterized and possibly highly variable cell types. Feasibility is demonstrated by validation with flow cytometry, immunohistochemistry and single-cell RNA-Seq analyses of human melanoma and colorectal tumor specimens. Altogether, our work not only improves accuracy but also broadens the scope of absolute cell fraction predictions from tumor gene expression data, and provides a unique novel experimental benchmark for immunogenomics analyses in cancer research.
Data availability
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Simultaneous enumeration of cancer and immune cell types from tumor gene expression dataPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE93722).
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Bioinformatics Approach to 2010-2011 TIV Influenza A/H1N1 Vaccine Immune ProfilingAvailable at ImmPort (accession no: SDY67).
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A Cell-based Systems Biology Assessment of Human Blood to Monitor Immune Responses After Influenza VaccinationPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE64655).
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Next generation sequencing of human immune cell subsets across diseasesPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE60424).
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RNA-Seq analysis of human adult peripheral blood populationsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE51984).
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Gene expression Classification of Colon Cancer defines six molecular subtypes with distinct clinical, molecular and survival characteristics [Expression]Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE39582).
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Single cell RNA-seq analysis of melanomaPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE72056).
Article and author information
Author details
Funding
Center for Advanced Modelling Science
- Julien Racle
- David Gfeller
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Project grant 31003A_173156)
- Julien Racle
- David Gfeller
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Patients involved in this study agreed to donate metastatic tissues upon informed consent, based on dedicated clinical investigation protocols established according to the relevant regulatory standards. The protocols were approved by the local IRB, i.e. the Commission cantonale d'éthique de la recherche sur l'être humain du Canton de Vaud.
Copyright
© 2017, Racle et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Simultaneous enumeration of cancer and immune cell types from bulk tumor gene expression data
eLife 6:e26476.
https://doi.org/10.7554/eLife.26476
Further reading
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The current understanding of humoral immune response in cancer patients suggests that tumors may be infiltrated with diffuse B cells of extra-tumoral origin or may develop organized lymphoid structures, where somatic hypermutation and antigen-driven selection occur locally. These processes are believed to be significantly influenced by the tumor microenvironment through secretory factors and biased cell-cell interactions. To explore the manifestation of this influence, we used deep unbiased immunoglobulin profiling and systematically characterized the relationships between B cells in circulation, draining lymph nodes (draining LNs), and tumors in 14 patients with three human cancers. We demonstrated that draining LNs are differentially involved in the interaction with the tumor site, and that significant heterogeneity exists even between different parts of a single lymph node (LN). Next, we confirmed and elaborated upon previous observations regarding intratumoral immunoglobulin heterogeneity. We identified B cell receptor (BCR) clonotypes that were expanded in tumors relative to draining LNs and blood and observed that these tumor-expanded clonotypes were less hypermutated than non-expanded (ubiquitous) clonotypes. Furthermore, we observed a shift in the properties of complementarity-determining region 3 of the BCR heavy chain (CDR-H3) towards less mature and less specific BCR repertoire in tumor-infiltrating B-cells compared to circulating B-cells, which may indicate less stringent control for antibody-producing B cell development in tumor microenvironment (TME). In addition, we found repertoire-level evidence that B-cells may be selected according to their CDR-H3 physicochemical properties before they activate somatic hypermutation (SHM). Altogether, our work outlines a broad picture of the differences in the tumor BCR repertoire relative to non-tumor tissues and points to the unexpected features of the SHM process.
