Inhibition of CD40 expression and CD40‐mediated dendritic cell function by tumor‐derived IL‐10

Abstract

As CD40 plays a key role in both antitumor immunity and DC maturation, we have studied the regulation of its expression during DC hematopoiesis (dendropoiesis) in vitro and in vivo in the tumor microenvironment. Using MC38 colon adenocarcinoma tumor models, we have demonstrated that DCs generated in vitro from bone marrow precursors obtained from tumor-bearers have significantly lower expression of CD40 molecules compared to DCs generated from tumor-free mice. Furthermore, CD40 expression on DCs isolated from the spleens of tumor-bearing mice was also significantly reduced, suggesting that tumor-derived factors inhibit CD40 expression on DCs during dendropoiesis both in vitro and in vivo. Interestingly, CD40 ligation on DCs generated from tumor-bearers did not result in inducible expression of IL-12 protein or IL-12 p40 mRNA. However, Staphylococcus aureus-induced IL-12 production by DCs was not altered in tumor-bearers, confirming that inhibition of IL-12 production by DCs generated in vitro from tumor-bearing mice was due to reduced expression of CD40 on DCs. We have also shown that MC38 tumor cells produce IL-10 and that exogenous IL-10 causes downregulation of CD40 expression on DCs. Key words: dendropoiesis; dendritic cell; immunosuppression; IL-10; CD40Escape from immune surveillance is a fundamental feature of tumors, which contributes to their uncontrolled growth, leading to death of the host. 1-3 The escape of malignant cells from immune recognition results from a defective function of cells of the immune system, including DCs, which play a key role in induction of specific immune responses. 4,5 Impairment of DC numbers and activity in cancer results in deficient expansion of specific CTLs and failure to eliminate tumor cells. 6 For example, alteration in the density and distribution of epidermal DCs in the peritumoral infiltrate of malignant melanoma may be responsible for determining the degree of T-cell activation. 7 Several studies have reported tumor-induced inhibition of DC function or differentiation. For instance, human DCs obtained from progressing chemotherapynonresponsive melanomas showed marked depression of CD86 expression and induction of anergy of syngeneic CD4 ϩ T cells. 8 Interestingly, this anergy could be overcome by showed that the ability of DCs isolated from breast cancer patients to stimulate allogeneic T lymphocytes was profoundly suppressed. Similar data were reported for human basal cell carcinoma DCs, which were deficient in CD80 and CD86 expression as well as in their ability to stimulate T-lymphocyte proliferation. 10 We demonstrated previously that tumor-derived factors not only cause premature apoptosis of DCs 11-15 but also significantly suppress DC generation and maturation in both murine and human cultures. 6,16 -19 Together, these data suggest that tumor-induced immune dysfunction is a generalized phenomenon and that determination of the mechanisms of DC dysfunction and protection of immune cells from tumor-induced disability is a crucial aspect of modern immunother...

Expression of the co-signaling molecules CD40-CD40L and their growth inhibitory effect on pancreatic cancer in vitro

“…However, the mechanism on how CD40 was involved in the process remained to be further investigated. Recent data showed that down-regulation of CD40 on DC cell surface and low-level CD40L on T cell surface of patients with pancreatic cancer impaired the function of DC cells, which was closely associated with the immunosuppressive status of cancer patients (26,27). Therefore, CD40 may be a valuable marker to predict the malignancy, invasive and metastatic potential and prognosis in pancreatic cancer patients.…”

Differential CD40/CD40L Expression Results in Counteracting Antitumor Immune Responses

“…Finally, if all the antitumor effects of CD40 were dependent on interaction with CD40L-mediated T cell activation, no antitumor effect would be observed in mice or human subjects lacking (or expressing less) CD40L or expressing nonfunctional mutant CD40L. In addition, impaired antitumor immune responses were associated with reduced expression of CD40L on T cells or CD40 on DC (21)(22)(23). The functional changes that occurred in those DC or T cells due to low CD40 or CD40L expressions are not yet understood.…”

Fusogenic membrane glycoprotein-mediated tumour cell fusion activates human dendritic cells for enhanced IL-12 production and T-cell priming

“…Tumour cells are known to exert a range of suppressive effects on DC via secretion of cytokines such as IL-10, IL-6, VEGF and M-CSF, or via cell surface interactions. [12][13][14][15] Although Mel888 secrete IL10, the suppression of DC activation was not IL-10 mediated in these experiments, since levels of secretion were similar from fusing and nonfusing tumour cells, and the addition of soluble IL-10 blocking receptors was unable to lift this suppression. …”