title: ICAM-1 has a critical role in the regulation of metastatic melanoma tumor susceptibility to CTL lysis by interfering with PI3K/AKT pathway.
abstract: Human primary melanoma cells (T1) were found to be more susceptible to lysis by a Melan-A/MART-1-specific CTL clone (LT12) than their metastatic derivative (G1). We show that this differential susceptibility does not involve antigen presentation by target cells, synapse formation between the metastatic target and CTL clone, or subsequent granzyme B (GrB) polarization. Although PI-9, an inhibitor of GrB, was found to be overexpressed in metastatic G1 cells, knockdown of the PI-9 gene did not result in the attenuation of G1 resistance to CTL-induced killing. Interestingly, we show that whereas T1 cells express high levels of intercellular adhesion molecule-1 (ICAM-1), a dramatically reduced expression was noted on G1 cells. We also showed that sorted ICAM-1+ G1 cells were highly sensitive to CTL-induced lysis compared with ICAM-1- G1 cells. Furthermore, incubation of metastatic G1 cells with IFN-gamma resulted in the induction of ICAM-1 and the potentiation of their susceptibility to lysis by LT12. More importantly, we found that the level of ICAM-1 expression by melanoma cells correlated with decreased PTEN activity. ICAM-1 knockdown in T1 cells resulted in increased phosphorylation of PTEN and the subsequent activation of AKT. We have additionally shown that inhibition of the phosphatidylinositol (3,4,5)-triphosphate kinase (PI3K)/AKT pathway by the specific inhibitor wortmannin induced a significant potentiation of susceptibility of G1 and ICAM-1 small interfering RNA-treated T1 cells to CTL-induced lysis. The present study shows that a shift in ICAM-1 expression, which was associated with an activation of the PI3K/AKT pathway, can be used by metastatic melanoma cells to escape CTL-mediated killing.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U753, Laboratoire d'Immunologie des Tumeurs Humaines: Interaction effecteurs cytotoxiques-système tumoral, Institut Gustave Roussy PR1 and IFR 54, Villejuif, France.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Hamaï
authors.forename: Franck
authors.initials: F
authors.lastname: Meslin
authors.forename: Houssem
authors.initials: H
authors.lastname: Benlalam
authors.forename: Abdelali
authors.initials: A
authors.lastname: Jalil
authors.forename: Maryam
authors.initials: M
authors.lastname: Mehrpour
authors.forename: Florence
authors.initials: F
authors.lastname: Faure
authors.forename: Yann
authors.initials: Y
authors.lastname: Lecluse
authors.forename: Philipe
authors.initials: P
authors.lastname: Vielh
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Avril
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
mesh_terms: D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004789:Enzyme Activation; D016193:G1 Phase / Q000276:immunology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000494:pharmacology; D058965:MART-1 Antigen; D008545:Melanoma / Q000201:enzymology / Q000276:immunology* / Q000556:secondary; D009363:Neoplasm Proteins / Q000276:immunology; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015843:Serpins / Q000096:biosynthesis / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; C102316:SERPINB9 protein, human; D015843:Serpins; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human