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
-
Simultaneous enumeration of cancer and immune cell types from tumor gene expression dataPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE93722).
-
Bioinformatics Approach to 2010-2011 TIV Influenza A/H1N1 Vaccine Immune ProfilingAvailable at ImmPort (accession no: SDY67).
-
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).
-
Next generation sequencing of human immune cell subsets across diseasesPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE60424).
-
RNA-Seq analysis of human adult peripheral blood populationsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE51984).
-
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).
-
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.
Metrics
-
- 2,086
- downloads
-
- 942
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
-
- Cancer Biology
Why does a normal cell possibly harboring genetic mutations in oncogene or tumor suppressor genes becomes malignant and develops a tumor is a subject of intense debate. Various theories have been proposed but their experimental test has been hampered by the unpredictable and improbable malignant transformation of single cells. Here, using an optogenetic approach we permanently turn on an oncogene (KRASG12V) in a single cell of a zebrafish brain that, only in synergy with the transient co-activation of a reprogramming factor (VENTX/NANOG/OCT4), undergoes a deterministic malignant transition and robustly and reproducibly develops within 6 days into a full-blown tumor. The controlled way in which a single cell can thus be manipulated to give rise to cancer lends support to the ‘ground state theory of cancer initiation’ through ‘short-range dispersal’ of the first malignant cells preceding tumor growth.
-
- Cancer Biology
Most human pancreatic ductal adenocarcinoma (PDAC) are not infiltrated with cytotoxic T cells and are highly resistant to immunotherapy. Over 90% of PDAC have oncogenic KRAS mutations, and phosphoinositide 3-kinases (PI3Ks) are direct effectors of KRAS. Our previous study demonstrated that ablation of Pik3ca in KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cells induced host T cells to infiltrate and completely eliminate the tumors in a syngeneic orthotopic implantation mouse model. Now, we show that implantation of Pik3ca−/− KPC (named αKO) cancer cells induces clonal enrichment of cytotoxic T cells infiltrating the pancreatic tumors. To identify potential molecules that can regulate the activity of these anti-tumor T cells, we conducted an in vivo genome-wide gene-deletion screen using αKO cells implanted in the mouse pancreas. The result shows that deletion of propionyl-CoA carboxylase subunit B gene (Pccb) in αKO cells (named p-αKO) leads to immune evasion, tumor progression, and death of host mice. Surprisingly, p-αKO tumors are still infiltrated with clonally enriched CD8+ T cells but they are inactive against tumor cells. However, blockade of PD-L1/PD1 interaction reactivated these clonally enriched T cells infiltrating p-αKO tumors, leading to slower tumor progression and improve survival of host mice. These results indicate that Pccb can modulate the activity of cytotoxic T cells infiltrating some pancreatic cancers and this understanding may lead to improvement in immunotherapy for this difficult-to-treat cancer.
