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 À /CD44 þ /ALDH þ 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. Cancer Res; 73(8); 2418-27. Ó2013 AACR.

Do Cancer Stem Cells have an Immunomodulatory Role Different from the Bulk of Tumor Cells?

“…This includes the ability to grow in anchorage independent conditions and to reestablish tumors in mice models even when a very small number of cells are transplanted. Interestingly, when breast cancer cells were induced to go through EMT process under the influence of the transcriptional factor Snail, an EMT inducing gene, they promoted the escape of breast cancer cells from T-cell mediated lysis by CD8+ cytotoxic T cells [65]. This further supports the role of CSCs in the immune escape of breast cancer cells.…”

Autophagy functions on EMT in gastrulation of avian embryo

“…20 Whereas breast cancer cells shows EMT phenotype along with the inducing of autophagy to resist cytotoxic T lymphocyte. 21 As a consequence, we have reasons to assume that autophagy does not only occur but also function in the period of embryonic gastrulation to some extent.…”

L’hypoxie tumorale

“…Les miR-302c et -520c ciblent l'expression de MICA et d'ULBP2 (UL16 binding protein 2), ligands activateurs des NK, et leur inhibition dans les cellules tumorales augmente la sensibilité de ces cellules aux NK [14]. L'hypoxie est capable de réguler l'expression de plusieurs miR [17]. Elle diminue, par exemple, l'expression de miR anti-oncogéniques, tels que miR-101, et augmente l'expression de miR pro-oncogéniques, tels que miR-21 et miR-210 [15,16].…”

“…En effet, l'expression de Snail dans des cellules de méla-nome inhibe la maturation des cellules dendritiques, induit une expansion des cellules Treg et rend les cellules tumorales résistantes à la lyse par les cellules T cytotoxiques [3]. L'expression de Snail dans des cellules de carcinome mammaire aboutit également à une résistance à la lyse par les CTL [17]. De plus, l'induction de la TEM dans ces cellules s'associe à une activation de l'autophagie impliquée dans la résistance aux cellules T ; le processus autophagique représenterait donc un mécanisme de résistance des cellules tumorales subissant la TEM [17].…”

“…L'expression de Snail dans des cellules de carcinome mammaire aboutit également à une résistance à la lyse par les CTL [17]. De plus, l'induction de la TEM dans ces cellules s'associe à une activation de l'autophagie impliquée dans la résistance aux cellules T ; le processus autophagique représenterait donc un mécanisme de résistance des cellules tumorales subissant la TEM [17]. L'hypoxie étant capable d'induire la TEM dans les cellules tumorales, le rôle des facteurs induisant la TEM dans la tolérance immune associée à l'hypoxie tumorale mérite d'être exploré.…”