title: Epithelial-to-mesenchymal transition and autophagy induction in breast carcinoma promote escape from T-cell-mediated lysis.
abstract: Epithelial-to-mesenchymal transition (EMT) mediates cancer cell invasion, metastasis, and drug resistance, but its impact on immune surveillance has not been explored. In this study, we investigated the functional consequences of this mode of epithelial cell plasticity on targeted cell lysis by cytotoxic T lymphocytes (CTL). Acquisition of the EMT phenotype in various derivatives of MCF-7 human breast cancer cells was associated with dramatic morphologic changes and actin cytoskeleton remodeling, with CD24(-)/CD44(+)/ALDH(+) stem cell populations present exhibiting a higher degree of EMT relative to parental cells. Strikingly, acquisition of this phenotype also associated with an inhibition of CTL-mediated tumor cell lysis. Resistant cells exhibited attenuation in the formation of an immunologic synapse with CTLs along with the induction of autophagy in the target cells. This response was critical for susceptibility to CTL-mediated lysis because siRNA-mediated silencing of beclin1 to inhibit autophagy in target cells restored their susceptibility to CTL-induced lysis. Our results argue that in addition to promoting invasion and metastasis EMT also profoundly alters the susceptibility of cancer cells to T-cell-mediated immune surveillance. Furthermore, they reveal EMT and autophagy as conceptual realms for immunotherapeutic strategies to block immune escape.
authors: Unité INSERM U753, Institut de Cancérologie Gustave Roussy, Villejuif, France.
authors: Intissar
authors: I
authors: Akalay
authors: Bassam
authors: B
authors: Janji
authors: Meriem
authors: M
authors: Hasmim
authors: Muhammad Zaeem
authors: MZ
authors: Noman
authors: Fabrice
authors: F
authors: André
authors: Patricia
authors: P
authors: De Cremoux
authors: Philippe
authors: P
authors: Bertheau
authors: Cécile
authors: C
authors: Badoual
authors: Philippe
authors: P
authors: Vielh
authors: Annette K
authors: AK
authors: Larsen
authors: Michèle
authors: M
authors: Sabbah
authors: Tuan Zea
authors: TZ
authors: Tan
authors: Joan Herr
authors: JH
authors: Keira
authors: Nicole Tsang Ying
authors: NT
authors: Hung
authors: Jean Paul
authors: JP
authors: Thiery
authors: Fathia
authors: F
authors: Mami-Chouaib
authors: Salem
authors: S
authors: Chouaib
mesh_terms: D001343:Autophagy; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010641:Phenotype; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D014408:Biomarkers, Tumor