B7-2–positive myeloma: incidence, clinical characteristics, prognostic significance, and implications for tumor immunotherapy

Abstract

Deficiencies in B7:CD28 costimulation are considered to be one of the major causes of the failure to generate a tumor-specific immune response. Up-regulating the expression of the B7 molecules on malignant B cells has been shown to stimulate cytotoxic T cells. Plasma cells from patients with myeloma express a tumor-specific idiotype but lack CD80 (B7-1) and have a variable expression of CD86 (B7-2). This study has identified the incidence and clinical significance of high CD86 expression on plasma cells at diagnosis and studied the ability of trimeric human CD40 ligand (huCD40LT) to up-regulate the expression of the B7 family on malignant plasma cells. CD86 expression on plasma cells was increased in 54% of the patients studied at diagnosis (n = 35) and was associated with a significantly shorter survival (median, 28 versus 57 months; χ2 = 4.6;P = .03) and a higher tumor load (patients with more than 50% bone marrow plasma cells, 47% versus 6%; χ2 = 7.2; P = .005). CD86 expression was highest on immature and primitive plasma cells (CD38++, CD45+) of both patients and controls and was associated with a CD40+, CD20+, CD19−, CD138+ phenotype. The shortened survival was associated with high CD86 only on mature (CD38++, CD45−) plasma cells (χ2 = 7.6; P = .006). There was no significant correlation between high CD86 and other known prognostic markers, including serum β2-microglobulin, serum thymidine kinase, and labeling index. The addition of huCD40LT to short-term cultures up-regulated both CD80 and CD86 expression on B cells (CD19+) and CD80 on plasma cells (CD38++), but did not up-regulate CD86 expression on plasma cells. Thus, B7-2–positive myeloma consists of a subgroup of patients with a relatively poor prognosis, and CD40LT may be useful in immunotherapy protocols because it up-regulates CD80 expression on malignant plasma cells without inducing B7-2–positive myeloma.

Adenovirus transduction to effect CD40 signalling improves the immune stimulatory activity of myeloma cells

“…Following infection with Ad-CD154, CD40 positive myeloma cells were induced to express higher levels of immune-accessory molecules. This is similar to what others have noted for myeloma cells cultured with recombinant soluble CD154 (Pope et al, 2000) or CD154-expressing fibroblasts (Urashima et al, 1995). Upregulation of these immune co-stimulatory molecules is associated with an enhanced capacity of Ad-CD154-infected myeloma cells to function as stimulatory cells in allogeneic MLR.…”

“…investigators (Pellat-Deceunynck et al, 1994;Tong et al, 1994;Pope et al, 2000). Nevertheless, we found that CD40 negative myeloma cells also could effect significantly greater proliferation in the MLR following infection with Ad-CD154, albeit less effectively than Ad-CD154-infected CD40 positive myeloma cells.…”

Soluble immune checkpoint molecules: Serum markers for cancer diagnosis and prognosis

“…46 However, in many hematological malignancies, cancerous cells express high levels of these molecules, especially the B7-2 or CD86, 47,48 which is associated with poor prognosis. 49,50 Concomitantly, elevated levels of sCD80 and sCD86 have been reported in patients with hematological malignancies. 51,52 sCD86 was found to be a significant prognostic marker in myeloma patients as well.…”

Circulating levels and clinical significance of soluble CD86 in myeloma patients

“…Both normal and leukaemic cells can express mCD86 and sCD86 transcript (Hirano et al , 1996; Zheng et al , 1998; Jeannin et al , 2000; Hock et al , 2002) and therefore both cell types are potential sources of circulating sCD86, which may be generated by either or both mechanisms. Although myeloma cells can express membrane CD86 (Pope et al , 2000) it is presently unknown whether they also express sCD86 transcript and if in fact they are a source of sCD86. The observation that only low levels of circulating sCD86 are observed in normal donors suggests that the high sCD86 levels observed in some myeloma patients are the result of sCD86 release either directly from, or as a response by other cells to, the malignant population.…”

“…However, many haemapoietic malignancies, including myeloma, constitutively express B7 and, in particular CD86, at relatively high levels (Hirano et al , 1996; Zheng et al , 1998). Malignant cell expression of membrane CD86 (mCD86) is associated with poor prognosis in both acute myeloid leukaemia (AML) and myeloma (Maeda et al , 1998; Pope et al , 2000). This suggests that other factors may modulate the immunostimulatory effects of membrane CD86 expression.…”