Epithelial-to-Mesenchymal Transition and Autophagy Induction in Breast Carcinoma Promote Escape from T-cell―Mediated Lysis

Epithelial-to-Mesenchymal Transition and Autophagy Induction in Breast Carcinoma Promote Escape from T-cell―Mediated Lysis

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 cyto...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Vol. 73; no. 8; pp. 2418 - 2427
Main Authors: AKALAY, Intissar, JANJI, Bassam, SABBAH, Michele, TUAN ZEA TAN, HERR KEIRA, Joan, TSANG YING HUNG, Nicole, THIERY, Jean Paul, MAMI-CHOUAIB, Fathia, CHOUAIB, Salem, HASMIM, Meriem, ZAEEM NOMAN, Muhammad, ANDRE, Fabrice, DE CREMOUX, Patricia, BERTHEAU, Philippe, BADOUAL, Cécile, VIELH, Philippe, LARSEN, Annette K
Format: Journal Article
Language:English
Published: Philadelphia, PA American Association for Cancer Research 15-04-2013
Subjects:
Antineoplastic agents
Autophagy
Biological and medical sciences
Biomarkers, Tumor - metabolism
Breast Neoplasms - genetics
Breast Neoplasms - immunology
Breast Neoplasms - metabolism
Carcinoma - genetics
Carcinoma - immunology
Carcinoma - metabolism
Cell Line, Tumor
Cytotoxicity, Immunologic
Epithelial-Mesenchymal Transition - genetics
Epithelial-Mesenchymal Transition - immunology
Female
Gynecology. Andrology. Obstetrics
Humans
Mammary gland diseases
Medical sciences
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Neoplastic Stem Cells - metabolism
Pharmacology. Drug treatments
Phenotype
T-Lymphocytes, Cytotoxic - immunology
Tumor Escape - immunology
Tumors
Mammary gland diseases
Breast carcinoma
Cytolysis
Breast disease
Induction
T-Lymphocyte
Breast cancer
Malignant tumor
Epithelial mesenchymal transition
Autophagy
Cancer
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Summary: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.
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ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-12-2432