Submitted June 4, 2008
Accepted November 18, 2008
Regulation of multiple myeloma survival and progression by CD1d
Emmanouil Spanoudakis, Ming Hu, Kikkeri Naresh, Evangelos Terpos, Valeria Melo, Alistair Reid, Ioannis Kotsianidis, Saad Abdalla, Amin Rahemtulla, and Anastasios Karadimitris*
Department of Haematology, Imperial College Healthcare NHS Trust, Hammersmith and St. Mary's Hospital, Imperial College London, London, United Kingdom
Department of Histopathology, Imperial College Healthcare NHS Trust, Hammersmith and St. Mary's Hospital, Imperial College London, London, United Kingdom
Department of Haematology and Medical Research, 251 General Air Force Hospital, Athens, Greece
Department of Haematology, Democritus University of Thrace Medical School, Alexandroupolis, Greece
* Corresponding author; email: a.karadimitris{at}imperial.ac.uk.
Downregulation of conventional HLA class I and II molecules from the surface of tumour cells is an important mechanism for tumour immune evasion, survival and progression. Whether CD1d, a non-conventional, glycolipid-presenting HLA class I-like molecule instructing the function of the immunoregulatory invariant NKT cells can affect tumour cell survival is not known.
Here we show that CD1d is highly expressed in pre-malignant 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 mAbs induces cell death of myeloma cell lines with restored CD1d expression and primary myeloma cells. Cell death induced by mAb engagement of CD1d is associated with over-expression of pro-apoptotic 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 co-operates with anti-myeloma 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 tumour survival and progression in humans.
