title: Proteasome inhibition blocks NF-κB and ERK1/2 pathways, restores antigen expression, and sensitizes resistant human melanoma to TCR-engineered CTLs.
abstract: Adoptive cell transfer (ACT) of ex vivo engineered autologous lymphocytes encoding high-affinity MART-1/HLA-A*0201-specific T-cell receptor (TCR)α/β chains (F5 CTL), densely infiltrate into sites of metastatic disease, mediating dramatic but partial clinical responses in patients with melanoma. We hypothesized that MART-1 downmodulation in addition to aberrant apoptotic/survival signaling could confer resistance to death signals delivered by transgenic CTLs. To explore this hypothesis, we established an in vitro model of resistant (R) lines from MART-1(+)/HLA-A*0201(+) F5 CTL-sensitive parental (P) lines under serial F5 CTL-selective pressure. We have recently reported that several melanoma R lines, while retaining MART-1 expression, exhibited constitutive NF-κB activation and overexpression of NF-κB-dependent resistance factors. Another established melanoma cell line M244, otherwise sensitive to F5 CTL, yielded R lines after serial F5 CTL-selective pressure, which had both reduced MART-1 expression levels, thus, could not be recognized, and were resistant to CTL-delivered apoptotic death signals. The proteasome inhibitor bortezomib blocked NF-κB activity, decreased phospho-ERK1/2, increased phospho-c-jun-NH(2)-kinase (p-JNK) levels, reduced expression of resistance factors, restored MART-1 expression to sufficient levels, which in combination allowed M244R lines be sensitized to F5 CTL killing. These findings suggest that proteasome inhibition in immune resistant tumors can restore proapoptotic signaling and improve tumor antigen expression.
authors.affiliation: Department of Surgery and the Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA 90095, USA. ajazirehi@mednet.ucla.edu
authors.forename: Ali R
authors.initials: AR
authors.lastname: Jazirehi
authors.forename: James S
authors.initials: JS
authors.lastname: Economou
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D058965:MART-1 Antigen / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism* / Q000637:transplantation
chemical_list: D000951:Antigens, Neoplasm; D001897:Boronic Acids; D058965:MART-1 Antigen; C548667:MLANA protein, human; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011948:Receptors, Antigen, T-Cell; D000069286:Bortezomib