Functional network pipeline reveals genetic determinants associated with in situ lymphocyte proliferation and survival of cancer patients

Bernhard Mlecnik, Gabriela Bindea, Helen K. Angell, Maria Stella Sasso, Anna C. Obenauf, Tessa Fredriksen, Lucie Lafontaine, Amelie M. Bilocq, Amos Kirilovsky, Marie Tosolini, Maximilian Waldner, Anne Berger, Wolf Herman Fridman, Arash Rafii Tabrizi, Viia Valge-Archer, Franck Pagès, Michael R. Speicher, Jérôme Galon

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

The tumor microenvironment is host to a complex network of cytokines that contribute to shaping the intratumoral immune reaction. Chromosomal gains and losses, coupled with expression analysis, of 59 cytokines and receptors and their functional networks were investigated in colorectal cancers. Changes in local expression for 13 cytokines were shown. Metastatic patients exhibited an increased frequency of deletions of cytokines from chromosome 4. Interleukin 15 (IL15) deletion corresponded with decreased IL15 expression, a higher risk of tumor recurrence, and reduced patient survival. Decreased IL15 expression affected the local proliferation of B and T lymphocytes. Patients with proliferating B and T cells at the invasive margin and within the tumor center had significantly prolonged disease-free survival. These results delineate chromosomal instability as a mechanism of modulating local cytokine expression in human tumors and underline the major role of IL15. Our data provide further mechanisms resulting in changes of specific immune cell densities within the tumor, and the importance of local active lymphocyte proliferation for patient survival.

Original languageEnglish
Article number228ra37
JournalScience Translational Medicine
Volume6
Issue number228
DOIs
Publication statusPublished - 19 Mar 2014

Fingerprint

Interleukin-15
Lymphocytes
Cytokines
Survival
Neoplasms
B-Lymphocytes
T-Lymphocytes
Chromosomal Instability
Chromosomes, Human, Pair 4
Cytokine Receptors
Tumor Microenvironment
Disease-Free Survival
Colorectal Neoplasms
Cell Count
Recurrence

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Functional network pipeline reveals genetic determinants associated with in situ lymphocyte proliferation and survival of cancer patients. / Mlecnik, Bernhard; Bindea, Gabriela; Angell, Helen K.; Sasso, Maria Stella; Obenauf, Anna C.; Fredriksen, Tessa; Lafontaine, Lucie; Bilocq, Amelie M.; Kirilovsky, Amos; Tosolini, Marie; Waldner, Maximilian; Berger, Anne; Fridman, Wolf Herman; Tabrizi, Arash Rafii; Valge-Archer, Viia; Pagès, Franck; Speicher, Michael R.; Galon, Jérôme.

In: Science Translational Medicine, Vol. 6, No. 228, 228ra37, 19.03.2014.

Research output: Contribution to journalArticle

Mlecnik, B, Bindea, G, Angell, HK, Sasso, MS, Obenauf, AC, Fredriksen, T, Lafontaine, L, Bilocq, AM, Kirilovsky, A, Tosolini, M, Waldner, M, Berger, A, Fridman, WH, Tabrizi, AR, Valge-Archer, V, Pagès, F, Speicher, MR & Galon, J 2014, 'Functional network pipeline reveals genetic determinants associated with in situ lymphocyte proliferation and survival of cancer patients', Science Translational Medicine, vol. 6, no. 228, 228ra37. https://doi.org/10.1126/scitranslmed.3007240
Mlecnik, Bernhard ; Bindea, Gabriela ; Angell, Helen K. ; Sasso, Maria Stella ; Obenauf, Anna C. ; Fredriksen, Tessa ; Lafontaine, Lucie ; Bilocq, Amelie M. ; Kirilovsky, Amos ; Tosolini, Marie ; Waldner, Maximilian ; Berger, Anne ; Fridman, Wolf Herman ; Tabrizi, Arash Rafii ; Valge-Archer, Viia ; Pagès, Franck ; Speicher, Michael R. ; Galon, Jérôme. / Functional network pipeline reveals genetic determinants associated with in situ lymphocyte proliferation and survival of cancer patients. In: Science Translational Medicine. 2014 ; Vol. 6, No. 228.
@article{3f975a1987274b5db382ccb66ac6881b,
title = "Functional network pipeline reveals genetic determinants associated with in situ lymphocyte proliferation and survival of cancer patients",
abstract = "The tumor microenvironment is host to a complex network of cytokines that contribute to shaping the intratumoral immune reaction. Chromosomal gains and losses, coupled with expression analysis, of 59 cytokines and receptors and their functional networks were investigated in colorectal cancers. Changes in local expression for 13 cytokines were shown. Metastatic patients exhibited an increased frequency of deletions of cytokines from chromosome 4. Interleukin 15 (IL15) deletion corresponded with decreased IL15 expression, a higher risk of tumor recurrence, and reduced patient survival. Decreased IL15 expression affected the local proliferation of B and T lymphocytes. Patients with proliferating B and T cells at the invasive margin and within the tumor center had significantly prolonged disease-free survival. These results delineate chromosomal instability as a mechanism of modulating local cytokine expression in human tumors and underline the major role of IL15. Our data provide further mechanisms resulting in changes of specific immune cell densities within the tumor, and the importance of local active lymphocyte proliferation for patient survival.",
author = "Bernhard Mlecnik and Gabriela Bindea and Angell, {Helen K.} and Sasso, {Maria Stella} and Obenauf, {Anna C.} and Tessa Fredriksen and Lucie Lafontaine and Bilocq, {Amelie M.} and Amos Kirilovsky and Marie Tosolini and Maximilian Waldner and Anne Berger and Fridman, {Wolf Herman} and Tabrizi, {Arash Rafii} and Viia Valge-Archer and Franck Pag{\`e}s and Speicher, {Michael R.} and J{\'e}r{\^o}me Galon",
year = "2014",
month = "3",
day = "19",
doi = "10.1126/scitranslmed.3007240",
language = "English",
volume = "6",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "228",

}

TY - JOUR

T1 - Functional network pipeline reveals genetic determinants associated with in situ lymphocyte proliferation and survival of cancer patients

AU - Mlecnik, Bernhard

AU - Bindea, Gabriela

AU - Angell, Helen K.

AU - Sasso, Maria Stella

AU - Obenauf, Anna C.

AU - Fredriksen, Tessa

AU - Lafontaine, Lucie

AU - Bilocq, Amelie M.

AU - Kirilovsky, Amos

AU - Tosolini, Marie

AU - Waldner, Maximilian

AU - Berger, Anne

AU - Fridman, Wolf Herman

AU - Tabrizi, Arash Rafii

AU - Valge-Archer, Viia

AU - Pagès, Franck

AU - Speicher, Michael R.

AU - Galon, Jérôme

PY - 2014/3/19

Y1 - 2014/3/19

N2 - The tumor microenvironment is host to a complex network of cytokines that contribute to shaping the intratumoral immune reaction. Chromosomal gains and losses, coupled with expression analysis, of 59 cytokines and receptors and their functional networks were investigated in colorectal cancers. Changes in local expression for 13 cytokines were shown. Metastatic patients exhibited an increased frequency of deletions of cytokines from chromosome 4. Interleukin 15 (IL15) deletion corresponded with decreased IL15 expression, a higher risk of tumor recurrence, and reduced patient survival. Decreased IL15 expression affected the local proliferation of B and T lymphocytes. Patients with proliferating B and T cells at the invasive margin and within the tumor center had significantly prolonged disease-free survival. These results delineate chromosomal instability as a mechanism of modulating local cytokine expression in human tumors and underline the major role of IL15. Our data provide further mechanisms resulting in changes of specific immune cell densities within the tumor, and the importance of local active lymphocyte proliferation for patient survival.

AB - The tumor microenvironment is host to a complex network of cytokines that contribute to shaping the intratumoral immune reaction. Chromosomal gains and losses, coupled with expression analysis, of 59 cytokines and receptors and their functional networks were investigated in colorectal cancers. Changes in local expression for 13 cytokines were shown. Metastatic patients exhibited an increased frequency of deletions of cytokines from chromosome 4. Interleukin 15 (IL15) deletion corresponded with decreased IL15 expression, a higher risk of tumor recurrence, and reduced patient survival. Decreased IL15 expression affected the local proliferation of B and T lymphocytes. Patients with proliferating B and T cells at the invasive margin and within the tumor center had significantly prolonged disease-free survival. These results delineate chromosomal instability as a mechanism of modulating local cytokine expression in human tumors and underline the major role of IL15. Our data provide further mechanisms resulting in changes of specific immune cell densities within the tumor, and the importance of local active lymphocyte proliferation for patient survival.

UR - http://www.scopus.com/inward/record.url?scp=84899050715&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84899050715&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.3007240

DO - 10.1126/scitranslmed.3007240

M3 - Article

VL - 6

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 228

M1 - 228ra37

ER -