This study has demonstrated that a substantial proportion of DCs in TB hosts have increased amount of lipids, specifically triglycerides. These results were obtained using different methods of lipid detection in several tumor models and also in cancer patients across several diagnoses. These findings were reproduced by using conditioned medium from tumor explants indicating that tumor-derived factors were responsible for the observed phenomenon. In this study we have tried to address two main questions: what is the mechanism of lipid accumulation in DCs and whether it has any functional consequences for these cells.
Accumulation of lipids could be due to increased synthesis of fatty acids or because of increased lipid uptake from plasma. Our data suggested that the second explanation is more likely (). Scavenger receptors represent a major route in acquiring fatty acids by DCs and macrophages 18
(see supplementary material
). Our results indicate that DCs from TB mice had preferential up-regulation of Msr1. This was consistent with the data demonstrating increased expression of Sra on macrophages during co-culture with ovarian tumor cells21
. DCs isolated from tumor tissues had substantially higher levels of Msr1 than cells isolated from spleens or LN, which paralleled the results with lipid level in these cells. Association between the expression of this receptor and lipid levels in DCs was further evident in the analysis of DC subsets. In our study accumulation of lipids and up-regulation of Msr1 was observed in cDC but not in pDCs. This was consistent with the results of a study that demonstrated that in contrast to cDCs, expression of Msr1 was not detectable in mouse and human pDCs22
. Our experiments with blocking of Msr1 with the soluble SR ligand fucoidan23
and specific antibody, as well as experiments with Msr1−/−
mice, have demonstrated that up-regulation of Sra was primarily responsible for increased uptake of exogenous lipids by DCs. It is likely that fatty acids are transferred to DCs in the form of modified lipoproteins. Different lipoprotein modifications have been described in cancer and those lipoproteins are likely abundant in tumor-bearing hosts24
. It is likely that accumulation of lipids by DCs in vitro
and in vivo
is due to the presence of tumor-derived factors that up-regulate the expression of Sra on DCs, which enable these cells to pick up modified lipoproteins from serum. The nature of those factors remain unclear and require further investigations (see supplementary material
In our studies lipid-laden DCs had a profound defect in ability to process and present soluble antigens. One possible explanation could be that lipid-laden DCs are immature cells, which are effective in picking up soluble proteins but have poor ability to present antigens. However, the fact that DC-HL and DC-NL expressed similar levels of MHC class II, and co-stimulatory molecules as well as the fact that peptide-loaded DC-HL and DC-NL stimulated specific T-cells equally well argues against this possibility. The molecular mechanisms by which fatty acids could affect antigen processing are currently not clear.
The results of the experiments with inhibition of fatty acid synthesis in TB mice demonstrated that this might improve DC function in TB host and antitumor immune responses and suggested that this approach could be useful in enhancing immune responses in cancer patients.