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.
authors.affiliation: INSERM UMRS1138, Laboratory of Integrative Cancer Immunology, Paris F-75006, France.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Mlecnik
authors.forename: Gabriela
authors.initials: G
authors.lastname: Bindea
authors.forename: Helen K
authors.initials: HK
authors.lastname: Angell
authors.forename: Maria Stella
authors.initials: MS
authors.lastname: Sasso
authors.forename: Anna C
authors.initials: AC
authors.lastname: Obenauf
authors.forename: Tessa
authors.initials: T
authors.lastname: Fredriksen
authors.forename: Lucie
authors.initials: L
authors.lastname: Lafontaine
authors.forename: Amelie M
authors.initials: AM
authors.lastname: Bilocq
authors.forename: Amos
authors.initials: A
authors.lastname: Kirilovsky
authors.forename: Marie
authors.initials: M
authors.lastname: Tosolini
authors.forename: Maximilian
authors.initials: M
authors.lastname: Waldner
authors.forename: Anne
authors.initials: A
authors.lastname: Berger
authors.forename: Wolf Herman
authors.initials: WH
authors.lastname: Fridman
authors.forename: Arash
authors.initials: A
authors.lastname: Rafii
authors.forename: Viia
authors.initials: V
authors.lastname: Valge-Archer
authors.forename: Franck
authors.initials: F
authors.lastname: Pagès
authors.forename: Michael R
authors.initials: MR
authors.lastname: Speicher
authors.forename: Jérôme
authors.initials: J
authors.lastname: Galon
mesh_terms: D049109:Cell Proliferation; D016207:Cytokines / Q000235:genetics; D006801:Humans; D008214:Lymphocytes / Q000473:pathology*; D009364:Neoplasm Recurrence, Local; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D015996:Survival Rate; D059016:Tumor Microenvironment
chemical_list: D016207:Cytokines