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 Blood, 12 March 2009, Vol. 113, No. 11, pp. 2498-2507.
Prepublished online as a Blood First Edition Paper on December 3, 2008; DOI 10.1182/blood-2008-06-161281.

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LYMPHOID NEOPLASIA

Regulation of multiple myeloma survival and progression by CD1d

Emmanouil Spanoudakis1,2, Ming Hu1, Kikkeri Naresh3, Evangelos Terpos4, Valeria Melo1, Alistair Reid1, Ioannis Kotsianidis2, Saad Abdalla1, Amin Rahemtulla1, and Anastasios Karadimitris1

1 Department of Haematology, Imperial College Healthcare National Health Service (NHS) Trust, Hammersmith and St Mary's Hospital, Imperial College London, London, United Kingdom; 2 Department of Haematology, Democritus University of Thrace Medical School, Alexandroupolis, Greece; 3 Department of Histopathology, Imperial College Healthcare NHS Trust, Hammersmith and St Mary's Hospital, Imperial College London, London, United Kingdom; and 4 Department of Haematology and Medical Research, 251 General Air Force Hospital, Athens, Greece

Down-regulation of conventional human leukocyte antigen (HLA) class I and II molecules from the surface of tumor cells is an important mechanism for tumor immune evasion, survival, and progression. Whether CD1d, a nonconventional, glycolipid-presenting HLA class I–like molecule instructing the function of the immunoregulatory invariant NKT cells can affect tumor cell survival is not known. Here we show that CD1d is highly expressed in premalignant and early myeloma, but with disease progression its expression is reduced and eventually in advanced stages and myeloma cell lines is lost altogether, suggesting that CD1d impacts negatively on myeloma cell survival. Consistent with this, engagement of CD1d by anti-CD1d monoclonal antibodies (mAbs) induces cell death of myeloma cell lines with restored CD1d expression and primary myeloma cells. Cell death induced by monoclonal antibody engagement of CD1d is associated with overexpression of proapoptotic Bax and mitochondrial membrane potential loss but it is caspase-activation independent; in addition, it requires the cytoplasmic tail but not the Tyr residue critical for lysosomal sorting of CD1d. Finally, anti-CD1d cooperates with antimyeloma agents in the killing of myeloma cells. Thus, this work provides evidence linking a novel function of CD1d in the regulation of cell death with tumor survival and progression in humans.


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