Cutting edge: bortezomib-treated tumors sensitized to NK cell apoptosis paradoxically acquire resistance to antigen-specific T cells.
Bortezomib augments caspase-8 activity, rendering tumors susceptible to NK cell lysis. We hypothesized this effect would likewise sensitize tumors to Ag-specific CTLs. Instead, bortezomib-treated tumors that acquired sensitivity to NK cells simultaneously became resistant to killing by Ag-specific CTLs. Reduction in CTL killing persisted for days, was not due to changes in tumor expression of MHC class I, and was overcome by pulsing tumors with peptides recognized by tumor-reactive CTLs. Tumor-outgrowth experiments showed tumors grew faster in SCID mice when cocultures of tumor-reactive CTLs and bortezomib-treated tumors were injected compared with untreated tumors (tumor doubling time 3.1 and 10.6 d, respectively; p < 0.01), whereas tumors grew slower in mice receiving cocultures of NK cells and bortezomib-treated tumors compared with untreated tumors (11.8 d and 5.0 d, respectively; p < 0.01). These findings demonstrate bortezomib-treated tumors sensitized to NK cell apoptosis paradoxically acquire resistance to CTLs as a consequence of bortezomib altering proteasomal processing and presentation of tumor Ags.
Lundqvist
Andreas
A
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Su
Su
S
Rao
Sheila
S
Childs
Richard
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002999:Clone Cells; D018920:Coculture Techniques; D003601:Cytotoxicity Tests, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D007113:Immunity, Innate; D007114:Immunization; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D011719:Pyrazines / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
D000970:Antineoplastic Agents; D001897:Boronic Acids; D018984:Epitopes, T-Lymphocyte; D011719:Pyrazines; D000069286:Bortezomib