Dysregulated Fas and Bcl-2 expression leading to enhanced apoptosis in T cells of multiple myeloma patients

Abstract

We have previously reported the presence of activated (HLA-DR+) T cells in multiple myeloma (MM) patients. These cells produce high amounts of interleukin (IL)-2 and interferon (IFN)-gamma and generate a potent antiplasma cell activity after appropriate in vitro stimulation, but they are unable in vivo to hold in check the disease. Activated T cells are highly susceptible to apoptosis, a form of programmed cell death involved in the modulation of immune responses and regulated by molecules such as Fas (CD95) and bcl-2. The aim of this study was to determine the expression of Fas and bcl-2 antigens and the susceptibility to apoptosis in T cells of MM patients. Fas+ cells were significantly higher, whereas bcl-2+ cells were significantly lower in MM patients than in the controls. MM patients with the highest number of HLA-DR+ T cells showed the highest Fas and the lowest bcl-2 expression. Two-color cytofluorometric analysis confirmed in individual cells that HLA-DR+ T cells coexpressed Fas and lacked bcl-2. Susceptibility to apoptosis was then investigated to evaluate the consequence of dysregulated Fas and bcl-2 expression. The percentage of apoptotic cells after incubation in medium alone (spontaneous apoptosis) or in the presence of methylprednisolone (MP) or anti-Fas monoclonal antibody (triggered apoptosis) was significantly higher in MM and mainly restricted to HLA-DR+ T cells. Spontaneous apoptotosis was reverted by exogenous IL-2. In conclusion, MM T cells have a dysregulated expression of Fas and bcl-2 antigens that is associated with an enhanced susceptibility to apoptosis. These data may unravel a novel mechanism by which activated MM T cells are weakened in their ability to exert an effective antitumor activity in vivo.

Transforming growth factor β from multiple myeloma cells inhibits proliferation and IL-2 responsiveness in T lymphocytes

“…Although there is good evidence that T cells have at least initially responded to the disease [4][5][6][7][8], these responses ultimately do not control MM. Failure to express costimulatory molecules by MM cells, and the induction of apoptosis in T cells by MM cells have been put forward as possible mechanisms for tumor cells to avoid or interfere with T cell responses.…”

“…T cells from patients have impaired responses to mitogens [2] and significantly lowered ability to generate LAK cells in response to interleukin-2 (IL-2) [3]. T cells from patients with MM have increased surface expression of Fas (APO-1/CD95), lower Bcl-2 expression, and are susceptible to apoptosis [4].…”

Increased expression of non‐functional killer inhibitory receptor CD94 in CD8+ cells of myeloma patients

“…The lack of activating forms may impair the activation of tumour‐specific T cells with low‐affinity TCR (Mandelboim et al , 1996); on the other hand, the lack of inhibitory forms in activated T cells may facilitate exaggerated signalling such as that observed during multivalent CD3 cross‐linking (Massaia et al , 1991). This may not necessarily result in a more effective immune activation, but may rather predispose to activation‐induced cell death, an intrinsic feature of chronically activated MM T cells (Massaia et al , 1995). Indeed, we have observed that repeated in vivo infusions of OKT3 and IL‐2 in MM patients do not boost T‐cell immunity but induce the opposite effect by triggering the apoptosis of activated T cells (Borrione et al , 1996).…”

“…Nevertheless, it is clear that T cells are unable to hold the disease in check, at least in its clinically evident stage. Our investigation of some of the mechanisms behind T‐cell dysfunction has shown that (1) MM T cells display a dysregulated bcl‐2 and Fas expression leading to enhanced susceptibility to spontaneous and induced apoptosis (Massaia et al , 1995) and (2) there are alterations in the molecular organization of the TCR–CD3 complex (Bianchi et al , 1997). These findings, however, provide only a partial explanation for the impaired ability of MM T cells to exert an effective anti‐tumour activity in vivo .…”

Dendritic cells generated from the blood of patients with multiple myeloma are phenotypically and functionally identical to those similarly produced from healthy donors

“…Evidence supporting the existence of Idreactive T cells in MM continues to accumulate (Moss et al, 1996). Initial attempts to stimulate this endogenous T-cell population and encourage a cytotoxic response against myeloma cells, using anti-CD3 antibody, has unfortunately met with poor clinical success (Massaia et al, 1995), and the acknowledgment that induction of in vivo cytotoxic T lymphocytes (CTL) is complex.…”