Induction of potent antitumor immunity by in situ targeting of intratumoral DCs

Abstract

Nonstandard abbreviations used: antigen (Ag); bone marrow (BM); CG-rich motif (CpG); complete medium (CM); control oligonucleotide (ODN-CTR); effector/target (E/T); Fms-like thyrosine kinase 3 ligand (Flt3L); Langerhans cell (LC); macrophage inflammatory protein-3α (MIP-3α); mean fluorescence intensity (MFI); T cell receptor (TCR). Conflict of interest:The authors have declared that no conflict of interest exists. IntroductionThe ability of tumors to escape the immune system has been a major obstacle to the development of effective tumor immunotherapy. Both central and peripheral immune tolerance have been implicated in the failure of tumor-bearing hosts to mount an immune response to their tumors. Central tolerance may play a fundamental role in the lack of response against self-tumor-associated antigens (Ag's), while peripheral tolerance may explain the lack of response against tumor-specific Ag's. DCs are believed to play a critical role in antitumor immune responses. These cells are the most potent APCs known, uniquely capable of inducing immunity to newly introduced Ag's (1, 2). Normally, DCs reside as immature cells in peripheral tissues where they sample the environment by taking up and processing local Ag's. In the presence of certain toll-like receptor ligands, these cells not only take up and process Ag's but also undergo activation and maturation and then migrate to the draining LNs where they prime specific CD4 and CD8 T cells to these Ag's. The presence in a wide range of tumors of immature DCs that are unable to stimulate T cells (3-9) suggests a possible role for these cells in the failure of tumor-bearing hosts to mount an effective antitumor response. This view is supported by a recent study in melanoma patients that showed that tumor-associated DCs are present mostly at the periphery of tumors and express low levels of costimulatory molecules, while the majority of T cells infiltrating tumors have a naive phenotype (10). The presence of naive but not memory or effector T cells in tumors may be related to the failure of tumoral DCs to provide an adequate stimulus or possibly to the induction of T cell tolerance by the immature DCs. By contrast to tumoral DCs, in vitro-generated DCs can induce an effective T cell-mediated antitumor immune response in vivo (11), indicating that the T cells of tumor-bearing hosts are capable of recognizing and responding to tumor Ag's and suggesting again that the tumor milieu prevents tumoral DCs from inducing an effective immune response. Indeed, injection of immature Ag-pulsed DCs can induce a specific tolerogenic response, while similarly pulsed DCs, when matured, induced a typical Th1 immune response (12).Based on the recognition of the central role of DCs in initiating immune responses, a variety of strategies have been devised to use DCs to stimulate immunity against tumor Ag's. Most of these strategies rely on the activation and maturation of DCs ex vivo and their subsequent reinfusion to tumor-bearing recipients after a pulse with tumor Ag's expressed as...

Tumor-specific dendritic cells generated by genetic redirection of Toll-like receptor signaling against the tumor-associated antigen, erbB2

“…Some antitumor effects have been observed using these strategies, [17][18][19][20] but it is not feasible to treat most patients in this manner. In addition, effective distribution of TLR agonists throughout the entire tumor mass is generally not feasible using simple injection at one site.…”

Efficient loading of dendritic cells following cryo and radiofrequency ablation in combination with immune modulation induces anti-tumour immunity

“…Recent studies using antigens coupled to antibodies directed against the mouse DC antigen DEC-205 (Steinman and Pope, 2002) or attraction of DC to the tumour via retrovirus-mediated expression of the DC-attracting chemokine CCL20 (Furumoto et al, 2004) illustrate the possibility to directly load tumour antigens onto DC in vivo. We previously showed in a murine model that the tumour debris left in the body after in situ tumour destruction by radiofrequency ablation is an in vivo tumour antigen source for the immune system.…”

Cross‐presentation of antigens from apoptotic tumor cells by liver sinusoidal endothelial cells leads to tumor‐specific CD8+ T cell tolerance

“…Furthermore, the function of DC presenting tumor-associated antigen and the quality of ensuing immune responses has to be seen in context of the local microenvironment. Increased recruitment of DC into the tumor, local activation of DC in the tumor and removal of CD4 + regulatory T cells from the tumor promote strong induction of tumorspecific immunity [41][42][43].…”

“…Furthermore, the function of DC presenting tumor-associated antigen and the quality of ensuing immune responses has to be seen in context of the local microenvironment. Increased recruitment of DC into the tumor, local activation of DC in the tumor and removal of CD4 + regulatory T cells from the tumor promote strong induction of tumorspecific immunity [41][42][43].While local factors determine tumor-specific immunity, formation of tumor metastasis in the liver is thought to be a consequence of immune escape. The liver appears to be involved in this process: first, tumor cells circulating in the blood stream are either trapped in the hepatic sinusoidal circulation due to the small vessel diameter or are arrested through mutual interaction with hepatic endothelial cells [2,44]; second, Kupffer cells, the large population of hepatic NK cells and liver endothelial cells itself have potent anti-tumor activity leading to killing of tumor cells trapped in the liver [5,25,45]; third, apoptotic tumor cell material is eliminated locally in the liver by APC (Fig.…”