Elevated serum soluble CD40 ligand in cancer patients may play an immunosuppressive role

Abstract

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-production decreased when stimulated T cells were cocultured with an increased amount of autologous MDSCs. The addition 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 CD25 high Foxp3), as well as induction of cytokines, such as IL-10 and IL-6. Moreover, sCD40L-induced enrichment 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. (Blood. 2012;120(15):3030-3038)

CD40 ligand‐expressing recombinant vaccinia virus promotes the generation of CD8+ central memory T cells

“…In contrast, following 24 h infection with VV-WT or rVV40L, lower, nonsignificant increases of CD80 and PD-L1 levels were detected on treated monocytes. Figure 2B shows data from one representative experiment and summarizes the results obtained in three independent assays.Notably, CD1a induction, suggestive of a dendritic cell differentiation was undetectable in all culture conditions (data not shown).Taken together, these data underline the different biological properties of membrane-bound CD40L, as provided by a rVV40L controlled infection, as compared to its soluble form, possibly reflecting a differential cross-linking of CD40 receptor expressed on the surfaces of CD14 + monocytes [24,[26][27][28]. …”

“…Taken together, these data underline the different biological properties of membrane-bound CD40L, as provided by a rVV40L controlled infection, as compared to its soluble form, possibly reflecting a differential cross-linking of CD40 receptor expressed on the surfaces of CD14 + monocytes [24,[26][27][28]. …”

“…Remarkably, activation of CD14 + cells by s40L, alone or in combination with VV-WT, was significantly less efficient in promoting the induction of IL-12p40 and IFN-type I gene expression. In sharp contrast, s40L, and, to a lower extent, VV-WT, but not rVV40L, appeared to promote the expression of IL-10 [24] and IDO [25] genes in treated CD14 + cells. Figure 2A reports data from three to five independent experiments.…”

“…On the other hand, importantly, at difference with s40L-stimulated monocytes, rVV40L-activated CD14 + cells do not express IL-10 [24] and IDO genes [27], thereby suggesting a highly effective capacity of activating T cells. In addition, rVV40L infection does not induce a marked upregulation of PD-L1 on nonprofessional APCs [26], at difference with cells treated with VV WT or s40L, thus suggesting that they are unlikely to induce exhaustion in activated T cells.…”

“…Therefore, gene expression and phenotypic profiles suggested that rVV40L-infected CD14 + monocytes might be highly effective APC, as indicated by the increased IL-12 and IFN-type I gene expression, the absence of IL-10 and IDO gene expression and by the limited expression of PD-L1 [23,24,26,27]. Based on these observations, we evaluated the ability of rVV40L-CD14 + monocytes to promote the differentiation of naïve CD8 + T cells into memory cells in different antigenic settings.…”