title: CD4⁺ follicular helper T cell infiltration predicts breast cancer survival.
abstract: CD4⁺ T cells are critical regulators of immune responses, but their functional role in human breast cancer is relatively unknown. The goal of this study was to produce an image of CD4⁺ T cells infiltrating breast tumors using limited ex vivo manipulation to better understand the in vivo differences associated with patient prognosis. We performed comprehensive molecular profiling of infiltrating CD4⁺ T cells isolated from untreated invasive primary tumors and found that the infiltrating T cell subpopulations included follicular helper T (Tfh) cells, which have not previously been found in solid tumors, as well as Th1, Th2, and Th17 effector memory cells and Tregs. T cell signaling pathway alterations included a mixture of activation and suppression characterized by restricted cytokine/chemokine production, which inversely paralleled lymphoid infiltration levels and could be reproduced in activated donor CD4⁺ T cells treated with primary tumor supernatant. A comparison of extensively versus minimally infiltrated tumors showed that CXCL13-producing CD4⁺ Tfh cells distinguish extensive immune infiltrates, principally located in tertiary lymphoid structure germinal centers. An 8-gene Tfh signature, signifying organized antitumor immunity, robustly predicted survival or preoperative response to chemotherapy. Our identification of CD4⁺ Tfh cells in breast cancer suggests that they are an important immune element whose presence in the tumor is a prognostic factor.
authors.affiliation: Molecular Immunology Unit, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Gu-Trantien
authors.forename: Sherene
authors.initials: S
authors.lastname: Loi
authors.forename: Soizic
authors.initials: S
authors.lastname: Garaud
authors.forename: Carole
authors.initials: C
authors.lastname: Equeter
authors.forename: Myriam
authors.initials: M
authors.lastname: Libin
authors.forename: Alexandre
authors.initials: A
authors.lastname: de Wind
authors.forename: Marie
authors.initials: M
authors.lastname: Ravoet
authors.forename: Hélène
authors.initials: H
authors.lastname: Le Buanec
authors.forename: Catherine
authors.initials: C
authors.lastname: Sibille
authors.forename: Germain
authors.initials: G
authors.lastname: Manfouo-Foutsop
authors.forename: Isabelle
authors.initials: I
authors.lastname: Veys
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haibe-Kains
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Singhal
authors.forename: Stefan
authors.initials: S
authors.lastname: Michiels
authors.forename: Françoise
authors.initials: F
authors.lastname: Rothé
authors.forename: Roberto
authors.initials: R
authors.lastname: Salgado
authors.forename: Hugues
authors.initials: H
authors.lastname: Duvillier
authors.forename: Michail
authors.initials: M
authors.lastname: Ignatiadis
authors.forename: Christine
authors.initials: C
authors.lastname: Desmedt
authors.forename: Dominique
authors.initials: D
authors.lastname: Bron
authors.forename: Denis
authors.initials: D
authors.lastname: Larsimont
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart
authors.forename: Christos
authors.initials: C
authors.lastname: Sotiriou
authors.forename: Karen
authors.initials: K
authors.lastname: Willard-Gallo
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D001943:Breast Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D016022:Case-Control Studies; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D020411:Oligonucleotide Array Sequence Analysis; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D059467:Transcriptome
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell