Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell–mediated lysis of myeloma

Abstract

IntroductionMultiple myeloma (MM) is a prototypic B-cell malignancy with overall survival varying from a few months to more than 15 years with melphalan-based autologous stem cell transplantation. 1 It is well established that patients with abnormal, especially hypodiploid karyotypes, and high lactic dehydrogenase have a worse prognosis. 2 Recently, we have reported that approximately 13% of MM patients have a high-risk prognostic score defined by the differential expression of 70 key genes, many of which are located on chromosome 1. 3 These patients have a poor outcome compared with low-risk patients, with inferior actuarial event-free survival (18% vs 60%, hazard ratio (HR) ϭ 4.51) and overall survival (28% vs 78%, HR ϭ 5.16) at 5 years despite intensive treatment on total therapy tandem transplantation regimens and the incorporation of novel agents, such as bortezomib into up-front management. 3 There is therefore a need for novel treatment approaches that target the melphalan-refractory myeloma stem cell pool in high-risk patients and synergize with currently available cytoreductive regimens.Killer-cell immunoglobulin-like receptor (KIR)-ligand (KIR-L) mismatched natural killer (NK) cells have potent antileukemic effects in the setting of heavily T cell-depleted haplo-identical allogeneic transplantation, but the majority of MM patients cannot tolerate the associated toxicity of such regimens. 4 However, we have recently demonstrated in a pilot trial that T cell-depleted haplo-identical KIR-L mismatched NK cells can be safely given to high-risk MM patients in the setting of an autologous transplantation without evidence of graft-versus-host disease. 5 Unfortunately, not all NK cells transfused are alloreactive; indeed, the majority are inhibited by patient human leukocyte antigen (HLA) class I, particularly HLA-C and -Bw4 molecules. 6 NK-cell activity is regulated by a dynamic balance between inhibitory and activating receptors that recognize ligands on target cells, with the inhibitory signals typically being dominant to prevent destruction by NK cells of healthy cells. [7][8][9][10][11] It has been postulated that mature NK cells express at least one inhibitory receptor for autologous HLA class I, thus preserving self-tolerance. In contrast, NK cells avidly lyse tumor cells that do not display such inhibitory KIR-L. A classic example is the cell line K562, which does not express HLA class I.HLA class I molecules consist of a major histocompatibility complex-encoded heavy chain, the light chain ␤ 2 -microglobulin (␤ 2 M), 12 and a third subunit, a peptide of 8 to 10 amino acids. 12,13 In humans, class I heavy chains are encoded by 3 loci, HLA-A, -B, and -C. The proteasome is responsible for the generation of peptides, which are transported to the endoplasmic reticulum. There they combine with HLA class I and ␤ 2 M, and are transported to the cell surface via the Golgi apparatus. 14 Binding of peptides to HLA class I is essential for the stability of HLA class I at the cell surface. HLA class I molecules/␤ 2...

Highly activated and expanded natural killer cells for multiple myeloma immunotherapy

“…[25][26][27][28] The activity and survival of human NK cells may be further enhanced by using IL15 which has not yet been applied in human trials, but has been shown to expand NK cell numbers in non-human primates. 29 Bortezomib could be utilized to down-regulate HLA class I molecules, 30 increase TRAILmediated apoptosis and up-regulate DNAM-1 and NKG2D ligands. [31][32][33] A phase II clinical trial has been initiated at our institution which examines the therapeutic effect of both allogeneic and autologous exp-NK cells for relapsed/refractory GEP-defined high-risk MM.…”

Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib

“…Encouraging preliminary results of these studies prompted us to evaluate the potential value of daratumumab in lenalidomide-and bortezomibrefractory multiple myeloma patients, who have a very poor prognosis at present. We hypothesized that, despite the drug resistance of the malignancy, the immune system of these patients could still respond to the previously described immunomodulatory effects of lenalidomide (11)(12)(13)(14) and bortezomib (15,16). Therefore, we now evaluated daratumumab alone or in combination with lenalidomide or bortezomib as a potential therapy for lenalidomide-and bortezomib-refractory patients.…”

Suppression of MG132-mediated cell death by peroxiredoxin 1 through influence on ASK1 activation in human thyroid cancer cells

“…PRDXs are currently known to possess six mammalian isoforms. Although their individual roles in cellular redox regulation and antioxidant protection are quite distinct, they all catalyze peroxide reduction to balance cellular H 2 O 2 levels essential for signaling and metabolism (Shi et al 2008). Besides their cytoprotective antioxidant function, PRDXs appear to play a role in cell proliferation, differentiation, immune response, protection of oxidant-sensitive proteins, regulation of cellular H 2 O 2 , control of apoptosis, and processes involving redox signaling (Shi et al 2008).…”