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Tumor cells can induce certain cytokines and soluble receptors that have a sup-pressive effect on the immune system. In this study, we showed that an extracellu-lar portion of a membrane-bound ligand of CD40 (soluble CD40 ligand; sCD40L) was significantly elevated in the serum of cancer patients compared with healthy donors. In addition, PBMCs from cancer patients had a relatively larger population of myeloid-derived suppressor cells (MDSCs), defined as CD33+HLA-DR” cells, and these cells expressed higher levels of CD40. T-cell proliferation and IFN-7 production decreased when stimulated T cells were cocultured with an increased amount of autologous MDSCs. The addi-tion of recombinant monomeric sCD40L enriched MDSCs and had an additive inhibitory effect on T-cell proliferation. PBMCs cultured in vitro with sCD40L also showed an expansion of regulatory T cells (CD4+CD25highFoxp3+), as well as Induction of cytokines, such as IL-10 and IL-6. Moreover, sCD40L-induced enrich-ment of programmed death-1-expressing T cells was greater in cancer patients than in healthy donors. Preexisting sCD40L also Inhibited IL-12 production from monocytes on activation. These data suggest that the higher levels of sCD40L seen in cancer patients may have an immunosuppressive effect. These studies were registered at www.clinicaltrials.gov as NCT00060528, NCT00019695, NCT00179309, NCT00514072, NCT00081848, and NCT00436956. [ABSTRACT FROM AUTHOR]