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RTRs, CKD patients and ICI-SCC(Pos) have increased MDSC frequencies and MDSC/DC ratios. These changes may impact on cancer immunosurveillance. Therefore, MDSC represent both a potential therapeutic target and prognostic marker in these patients, with respect to the development of SCC and other malignancies.

SummaryHuman polymorphonuclear leucocytes (PMN) are thought to be immunosuppressive. The suppressive mechanism(s) used by PMN are, however, not well defined and in this study they were analysed using T-cell responses to CD3 + CD28 monoclonal antibodies (mAb) as a readout. We demonstrate that in vitro activated PMN (PMN act ) can, without any T-cell interaction, induce apparent T-cell suppression by inhibiting the stimulatory capacity of the CD3 mAb. However, a cell-directed suppression of Tcell proliferation was observed when PMN act were added to pre-activated T cells that are already committed to polyclonal proliferation. This suppression was partially reversed by catalase addition (P < 0Á01) and largely reversed by addition of exogenous interleukin-2 (P < 0Á001) but was not significantly reduced by nitric oxide synthase inhibition, myeloperoxidase inhibition or addition of excess arginine. Following removal of PMN act , suppressed T cells could respond normally to further stimulation. In addition to suppressing proliferation, co-culture with PMN act also induced a significant decrease in T-cell viability that was reversed by catalase addition (P < 0Á05). The addition of the arginase inhibitor N-hydroxy-nor-L-arginine induced both a further significant, catalase-sensitive, loss in T-cell viability and increased nitrite release (P < 0Á001). These data demonstrate that PMN, when activated, can both induce T-cell death and reversibly inhibit proliferation of activated T cells. The mechanisms underlying these distinct processes and the effects of arginase inhibitors on PMN induced cytotoxicity merit further investigation.

The release of soluble forms of CD80 (sCD80), CD86 (sCD86), and CD83 (sCD83) provide a potentially powerful immunoregulatory mechanism. We therefore investigated the potential presence and relative levels of these molecules in the synovial fluid (SF) and serum of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Serum and SF levels were measured by enzyme-linked immunosorbent assay. Serum levels of sCD80, sCD86, and sCD83 in RA and OA patients were similar to those present in normal donor serum (NDS) and the SF of OA patients. In contrast, when compared with NDS and OA SF levels, almost all RA SF samples had elevated sCD83 levels (32/35, >0.63 ng/ml) and a substantial proportion had elevated sCD80 (13/29, >0.22 ng/ml) or sCD86 (16/33, >2.31 ng/ml) levels. Analysis of matched pairs of serum and SF from RA patients demonstrated that the SF/serum ratio for sCD80 (95% CI = 1.7-3), sCD86 (95% CI = 1.5-3.1), and sCD83 (95% CI = 3.6-7.8) levels was >1 in almost all patients. In conclusion, this study shows that the SF from almost all RA patients contain elevated levels of sCD83 and the majority of these samples also contain elevated levels of sCD80 and/or sCD86. These molecules may play a role in modulating immune responses within the rheumatoid joint.

BACKGROUNDCD40 plays a critical role in immunoregulation, and CD40 ligation is being investigated as a therapy for hematologic malignancies. Although soluble CD40 (sCD40) is a potential modulator of both antitumor responses and CD40‐based therapies, the levels and significance of sCD40 in patients with hematologic malignancies are unknown.METHODSThe authors evaluated serum/plasma sCD40 levels using an enzyme‐linked immunoassay in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and multiple myeloma (MM).RESULTSLevels of sCD40 were elevated in serum (>1.697 ng/mL) or plasma (>0.649 ng/mL) from 73% of patients with CLL, 80% of patients with MCL, 40% of patients with AML, 43% of patients with MDS, and 33% of patients with MM. Multivariate analysis of patients with MM demonstrated that elevated sCD40 was a significant, independent predictor of poor survival. In multivariate analysis of patients with AML, sCD40 was a significant prognostic factor when the interaction of age and sCD40 was included as a variable. Further analysis demonstrated that elevated sCD86 levels were associated with significantly shorter survival only in AML patients younger than age 64 years. Release of sCD40 by CLL cells was induced by cross‐linking with CD40 monoclonal antibody.CONCLUSIONSMany patients with hematologic malignancies have elevated circulating levels of sCD40, and these elevated levels are associated with a poor prognosis at least in patients with MM and AML, suggesting that sCD40 may have a role in modulating antitumor responses and also may be a useful prognostic marker. In addition, the findings suggested that further studies will be required to determine the effect of circulating sCD40 on the clinical effectiveness of CD40‐ligating reagents used in the treatment of hematologic malignancies. Cancer 2006. © 2006 American Cancer Society.

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Summary Circulating soluble CD86 (sCD86) levels are elevated in a number of leukaemias and are an independent prognostic factor in acute myeloid leukaemia. We investigated the clinical significance of circulating sCD86 in 299 patients from the UK Medical Research Council myeloma VIth trial, where patients received ABCM [adriamycin, carmustine (BCNU), cyclophosphamide, melphalan] either alone or with prednisolone (ABCM + P). Serum levels of sCD86 were significantly elevated (P = 0·0001) in myeloma patients and using the median normal donor level (0·621 ng/ml) as a cut‐off point, 70% of patients had elevated levels (range = 0·015–15·87 ng/ml, median = 1·1 ng/ml). In univariate analysis elevated sCD86 levels were associated with significantly shorter (P < 0·001) survival (median = 22 vs. 51 months) and event‐free survival (median = 14 vs. 31 months) in ABCM + P but not ABCM patients. Multivariate analysis demonstrated that sCD86 was a significant, independent prognostic marker of both overall [risk ratio (RR) = 2·04, P = 0·0006] and event‐free (RR = 1·95, P = 0·0004) survival in ABCM + P patients. In conclusion, this study demonstrated that sCD86 levels are a significant independent prognostic marker in at least some myeloma treatment groups and its biological role and prognostic value should be further investigated.

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