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

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Abstract

We introduce the Microenvironment Cell Populations-counter (MCP-counter) method, which allows the robust quantification of the absolute abundance of eight immune and two stromal cell populations in heterogeneous tissues from transcriptomic data. We present in vitro mRNA mixture and ex vivo immunohistochemical data that quantitatively support the validity of our method’s estimates. Additionally, we demonstrate that MCP-counter overcomes several limitations or weaknesses of previously proposed computational approaches. MCP-counter is applied to draw a global picture of immune infiltrates across human healthy tissues and non-hematopoietic human tumors and recapitulates microenvironment-based patient stratifications associated with overall survival in lung adenocarcinoma and colorectal and breast cancer.

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Most cited references 11

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Effector memory T cells, early metastasis, and survival in colorectal cancer.

Franck Pagès, Anne Berger, Matthieu Camus … (2005)

The role of tumor-infiltrating immune cells in the early metastatic invasion of colorectal cancer is unknown. We studied pathological signs of early metastatic invasion (venous emboli and lymphatic and perineural invasion) in 959 specimens of resected colorectal cancer. The local immune response within the tumor was studied by flow cytometry (39 tumors), low-density-array real-time polymerase-chain-reaction assay (75 tumors), and tissue microarrays (415 tumors). Univariate analysis showed significant differences in disease-free and overall survival according to the presence or absence of histologic signs of early metastatic invasion (P<0.001). Multivariate Cox analysis showed that an early conventional pathological tumor-node-metastasis stage (P<0.001) and the absence of early metastatic invasion (P=0.04) were independently associated with increased survival. As compared with tumors with signs of early metastatic invasion, tumors without such signs had increased infiltrates of immune cells and increased levels of messenger RNA (mRNA) for products of type 1 helper effector T cells (CD8, T-BET [T-box transcription factor 21], interferon regulatory factor 1, interferon-gamma, granulysin, and granzyme B) but not increased levels of inflammatory mediators or immunosuppressive molecules. The two types of tumors had significant differences in the levels of expression of 65 combinations of T-cell markers, and hierarchical clustering showed that markers of T-cell migration, activation, and differentiation were increased in tumors without signs of early metastatic invasion. The latter type of tumors also had increased numbers of CD8+ T cells, ranging from early memory (CD45RO+CCR7-CD28+CD27+) to effector memory (CD45RO+CCR7-CD28-CD27-) T cells. The presence of high levels of infiltrating memory CD45RO+ cells, evaluated immunohistochemically, correlated with the absence of signs of early metastatic invasion, a less advanced pathological stage, and increased survival. Signs of an immune response within colorectal cancers are associated with the absence of pathological evidence of early metastatic invasion and with prolonged survival. Copyright 2005 Massachusetts Medical Society.

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Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy.

David G DeNardo, Donal J Brennan, Elton Rexhepaj … (2011)

Immune-regulated pathways influence multiple aspects of cancer development. In this article we demonstrate that both macrophage abundance and T-cell abundance in breast cancer represent prognostic indicators for recurrence-free and overall survival. We provide evidence that response to chemotherapy is in part regulated by these leukocytes; cytotoxic therapies induce mammary epithelial cells to produce monocyte/macrophage recruitment factors, including colony stimulating factor 1 (CSF1) and interleukin-34, which together enhance CSF1 receptor (CSF1R)-dependent macrophage infiltration. Blockade of macrophage recruitment with CSF1R-signaling antagonists, in combination with paclitaxel, improved survival of mammary tumor-bearing mice by slowing primary tumor development and reducing pulmonary metastasis. These improved aspects of mammary carcinogenesis were accompanied by decreased vessel density and appearance of antitumor immune programs fostering tumor suppression in a CD8+ T-cell-dependent manner. These data provide a rationale for targeting macrophage recruitment/response pathways, notably CSF1R, in combination with cytotoxic therapy, and identification of a breast cancer population likely to benefit from this novel therapeutic approach. These findings reveal that response to chemotherapy is in part regulated by the tumor immune microenvironment and that common cytotoxic drugs induce neoplastic cells to produce monocyte/macrophage recruitment factors, which in turn enhance macrophage infiltration into mammary adenocarcinomas. Blockade of pathways mediating macrophage recruitment, in combination with chemotherapy, significantly decreases primary tumor progression, reduces metastasis, and improves survival by CD8+ T-cell-dependent mechanisms, thus indicating that the immune microenvironment of tumors can be reprogrammed to instead foster antitumor immunity and improve response to cytotoxic therapy.

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Genomic Analysis of Immune Cell Infiltrates Across 11 Tumor Types.

Michael Iglesia, Joel S. Parker, Katherine A. Hoadley … (2016)

Immune infiltration of the tumor microenvironment has been associated with improved survival for some patients with solid tumors. The precise makeup and prognostic relevance of immune infiltrates across a broad spectrum of tumors remain unclear.

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Author and article information

Contributors

Aurélien de Reyniès: aurelien.DeReynies@ligue-cancer.net

Journal

Journal ID (nlm-ta): Genome Biol

Journal ID (iso-abbrev): Genome Biol

Title: Genome Biology

Publisher: BioMed Central (London )

ISSN (Print): 1474-7596

ISSN (Electronic): 1474-760X

Publication date (Electronic): 20 October 2016

Publication date PMC-release: 20 October 2016

Publication date Collection: 2016

Volume: 17

Electronic Location Identifier: 218

Affiliations

[1 ]INSERM UMR_S 1138, Cancer, Immune Control and Escape, Cordeliers Research Centre, Paris, France

[2 ]Université Paris Descartes, Paris, France

[3 ]Université Pierre et Marie Curie, Paris, France

[4 ]Programme Cartes d’Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France

[5 ]Centre de Recherche en Cancérologie de Toulouse, Unité Mixte de Recherche, 1037 INSERM, Université Toulouse III, Toulouse, France

[6 ]Department of Pathology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France

[7 ]INSERM, UMR_S1147, Paris, France

Article

Publisher ID: 1070

DOI: 10.1186/s13059-016-1070-5

PMC ID: 5073889

PubMed ID: 27765066

SO-VID: 0a46e9eb-651f-454d-90ca-2753813cc227

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 3 August 2016

Date accepted : 21 September 2016

Funding

Funded by: INSERM

Funded by: FundRef http://dx.doi.org/10.13039/501100005413, Université Paris Descartes;

Funded by: FundRef http://dx.doi.org/10.13039/501100005737, Université Pierre et Marie Curie;

Funded by: CARPEM

Funded by: Labex Immuno-Oncology

Award ID: LAXE62_9UMS872 FRIDMAN

Award Recipient : Catherine Sautès-Fridman

Funded by: Fondation ARC pour la Recherche sur le Cancer (FR)

Funded by: Cancéropôle Ile-de-France

Funded by: Institut National Du Cancer (FR)

Award ID: 2011-1-PLBIO-06-INSERM 6-1,PLBIO09-088-IDF-KROEMER

Award Recipient : Catherine Sautès-Fridman

Funded by: Universidad de los Andes School of Medicine

Funded by: Colciencias

Funded by: Ecole doctorale Physiologie, physiopathologie et thérapeutique

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ScienceOpen disciplines: Genetics

Keywords: transcriptomic markers,gene signatures,deconvolution,tumor microenvironment

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ScienceOpen disciplines: Genetics

Keywords: transcriptomic markers, gene signatures, deconvolution, tumor microenvironment

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

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Most cited references 11

Effector memory T cells, early metastasis, and survival in colorectal cancer.

Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy.

Genomic Analysis of Immune Cell Infiltrates Across 11 Tumor Types.

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