Induction of potent NK cell-dependent anti-myeloma cytotoxic T cells in response to combined mapatumumab and bortezomib

Paul J. Neeson, Andy K Hsu, Yin R. Chen, Heloise M Halse, Joanna Kejun Loh, Reece Cordy, Kate Fielding, Joanne E Davis, Josh Noske, Alex J. Davenport, Camilla A. Lindqvist-Gigg, Robin Humphreys, Tsin Tai, H Miles Prince, Joseph A. Trapani, Mark J Smyth, David S Ritchie

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3 Citations (Scopus)

Abstract

There is increasing evidence that some cancer therapies can promote tumor immunogenicity to boost the endogenous antitumor immune response. In this study, we used the novel combination of agonistic anti-TRAIL-R1 antibody (mapatumumab, Mapa) with low dose bortezomib (LDB) for this purpose. The combination induced profound myeloma cell apoptosis, greatly enhanced the uptake of myeloma cell apoptotic bodies by dendritic cell (DC) and induced anti-myeloma cytotoxicity by both CD8+ T cells and NK cells. Cytotoxic lymphocyte expansion was detected within 24 h of commencing therapy and was maximized when myeloma-pulsed DC were co-treated with low dose bortezomib and mapatumumab (LDB+Mapa) in the presence of NK cells. This study shows that Mapa has two distinct but connected modes of action against multiple myeloma (MM). First, when combined with LDB, Mapa produced powerful myeloma cell apoptosis; secondly, it promoted DC priming and an NK cell-mediated expansion of anti-myeloma cytotoxic lymphocyte (CTL). Overall, this study indicates that Mapa can be used to drive potent anti-MM immune responses.

Original languageEnglish
Article numbere1038011
Number of pages16
JournalOncoImmunology
Volume4
Issue number9
DOIs
Publication statusPublished - Sep 2015
Externally publishedYes

Keywords

  • Dendritic cell
  • Multiple myeloma
  • Natural killer cell
  • Proteasome inhibitor
  • T cell
  • Tumor necrosis factor apoptosis inducing ligand and receptor

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