Identification of target actin content and polymerization status as a mechanism of tumor resistance after cytolytic T lymphocyte pressure.
To investigate tumor resistance to T cell lysis, a resistant variant was selected after specific cytolytic T lymphocytes (CTL) selection pressure. Although the resistant variant triggered perforin and granzyme B transcription in specific CTLs, as well as their degranulation, it exhibited a dramatic resistance to cytotoxic T cell killing. It also displayed strong morphological changes with alterations of the actin cytoskeleton. Electron microscopy analysis revealed a loosen interaction between CTLs and the resistant variant despite the formation of apparently normal conjugates. Transcriptional profiling identified a gene expression signature that distinguished sensitive from resistant tumor targets. More notably, we found that actin-related genes ephrin-A1 and scinderin were overexpressed in resistant target. Silencing of these genes using RNA interference resulted in a restoration of normal cell morphology and a significant attenuation of variant resistance to CTL killing. Our present study shows that a shift in cytoskeletal organization can be used, by tumor cells, as a strategy to promote their resistance after CTL selection pressure.
Abouzahr
Soraya
S
Institut Gustave Roussy, Institut National de la Santé et de la Recherche Médicale U487, 94805 Villejuif, France.
Bismuth
Georges
G
Gaudin
Catherine
C
Caroll
Oliver
O
Van Endert
Peter
P
Jalil
Abdelali
A
Dausset
Jean
J
Vergnon
Isabelle
I
Richon
Catherine
C
Kauffmann
Audrey
A
Galon
Jérôme
J
Raposo
Graca
G
Mami-Chouaib
Fathia
F
Chouaib
Salem
S
D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D036382:Ephrin-A1 / Q000737:chemistry; D018260:Gelsolin / Q000378:metabolism; D020868:Gene Silencing; D014644:Genetic Variation; D006801:Humans; D047468:Immunoprecipitation; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009369:Neoplasms / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011108:Polymers / Q000737:chemistry*; D011312:Pressure; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic
D000199:Actins; D036382:Ephrin-A1; D018260:Gelsolin; D011108:Polymers; C065395:scinderin