Figure 1. The impact of tumor-derived factors on antigen presentation by DCs.

Immune escape by tumors is based on two main mechanisms. One mechanism is to directly become “invisible” to immune cells. Mutations in MHC-I and downregulation TAP or ERAP lead to reduced surface expression of peptide-loaded MHC-I. Tumor cells can also express the non-classical MHC molecule HLA-G that can lead to T cell tolerance. Another mechanism is by indirectly escaping immune surveillance by impacting APCs activation and function. Tumor-derived IL-6, IL-10, VEGF and other unidentified factors inhibit production of IL-12 and decrease expression of peptide-MHC-II, costimulatory molecules, and the LN homing receptor CCR7 on the DC surface. Tumor-derived IL-6 and IL-10 activate the transcription factor STAT3, which suppresses DC maturation and promotes DC dysfunction. These cytokines also induce autocrine production of IL-6 and IL-10 in DCs, which further augments STAT3 signaling. Tumor-derived TSLP upregulates OX40L, which, together with reduced expression of IL-12, promotes DC-based skewing of T cell differentiation towards the tumor-supporting T_H2 phenotype instead of the anti-tumor T_H1 or T_H17 phenotype that support CD8 T cell expansion. The tumor environment can also induce regulatory DCs, possibly by enhancing expression of the transcription factor Satb1. Tumors also promote Galectin-1, TGF-β, and IDO production in DCs, thereby leading to Treg generation. Finally, upregulation of the scavenger receptor Msr1 leads to enhanced lipid uptake and results in impaired antigen presentation by DCs. Additional defects in MHC-II expression, including downregulation of CIITA and impaired removal of the MHC-II CLIP peptide, have been observed in malignant B cells, however it remains to be determined if these changes also occur in DCs in the tumor microenvironment.