TLR are pattern recognition receptors for pathogen-associated molecular patterns (PAMP) and endogenous molecules released from injured and necrotic cells (DAMP) (Kumar et al.2009). This in turn leads to the reversal of immune tolerance elicited by Tregs (Kong et al.2009). Also, the amount of tumor-infiltrating Tregs is reduced with imatinib therapy (Larmonier et al. 2008).
Miyara et al.2009), human CD4+ T cells with suppressor function (in vitro) were shown to have two major phenotypes, including Foxp3loCD45RA+ resting Tregs (rTregs) and CD45RAFoxp3hi-activated Tregs (aTregs). This reagent severely depletes Tregs and improves antitumor vaccines in mice (Litzinger et al.2007). Furthermore, antigen-presenting cells (APC), such as dendritic cells (DC), macrophages, and granulocytes, can recognize non-self structures via toll-like receptors (TLR) or C-type lectin receptors (CLRs) (Janeway 1989). ;Figdor et al. 2002).
Such self-reactive T cells regulate regulatory (Treg) CD4+CD25+T cells (peripheral tolerance) (Vignali et al. 2008). These cells appear to be involved in the recently described innate immunity against tumor cells (Cui et al. 2003). CTLA-4 expression and function can be regulated by anti-CTLA4 antibody therapy (Quezada et al. 2008).
Downregulation of VEGF further avoids interfering with DC generation and maturation (Wang et al. 2004). Some of these therapies have produced substantial results (especially ACT), while other strategies have been less successful (cancer vaccines), or produced significant adverse effects (severe autoimmunity in patients treated with anti-CTLA-4 ) (Phan et al. 2003). Furthermore, blockade of VEGF in tumor-bearing mice partially reverses thymic atrophy (Ohm et al. 2003).
ETBR can promote angiogenesis indirectly by upregulating VEGF production in blood vessels (Jesmin et al. 2006). Our laboratory has recently demonstrated a novel role for ETBR in tumor immunotherapy (Buckanovich et al. 2008). Bataille et al.1989), because a similar syndrome was observed in our neuroblastoma trials (described below).
Human Dendritic Cell Subsets
At steady state, unactivated (immature) DCs present self-antigens to T cells, resulting in tolerance (Hawiger et al. 2001; Steinman et al. 2003). Once activated (mature), antigen-loaded DCs are directed to trigger antigen-specific immunity (Finkelman et al. 1996; Brimnes et al. 2003), leading to T cell proliferation and differentiation into helper and effector cells. Our recent studies in humans show that the acquisition of Tfh phenotype and function is dependent on IL-12p70 (Schmitt et al. 2009).
DCs reside in the tissue where they are ready to capture antigens (Geissmann et al.2010). Antigen can also reach draining lymph nodes without the involvement of peripheral tissue DCs and be captured and presented by lymph node resident DCs (Itano et al.2003). These findings may explain the modest clinical efficacy of systemic IL-12 administration in cancer patients (Motzer et al.2001; Cheever2008).
LCs induce robust proliferation of naïve allogeneic CD8+T cells when compared to CD14+DCs (Klechevsky et al.2008). Therefore, they are extremely more efficient at killing target cells; in particular, tumor cells that express low levels of peptide/HLA complexes (Klechevsky et al. 2008). IL-15 may explain the remarkable effects of LCs in the development of cytotoxic T lymphocyte (CTL) responses (Mohamadzadeh et al.2001; Dubsky et al.2007; Klechevsky et al.2009).
Plasmacytoid DCs (pDCs) are considered the frontline of antiviral immunity due to their ability to rapidly produce large amounts of type I interferon (Siegal et al. 1999; Liu 2005). Human pDCs actually consist of two subsets, distinguished by the expression of CD2 (Matsui et al.2009).
DCs in Tumor Environment
This inhibition appears to be dependent on the binding of ILT7 to pDC, which interacts with BST2 expressed on tumor cells (Cao et al. 2009). Similarly, in ovarian carcinoma, tumor-infiltrating pDCs do not induce effector CD8+ T-cell responses, but promote the differentiation of IL10+CCR7+CD8+Tregs (Wei et al. 2005). Finally, pDCs can promote tumor angiogenesis by secreting pro-angiogenic cytokines (Curiel et al. 2004; Coukos et al. 2005).
DC can fight tumors through at least two pathways: indirect through the induction of strong CTL responses and direct through DC-dependent tumor cytotoxicity. For example, pDCs appear to directly contribute to the in vivo antitumor activity of imiquimod (a TLR7 ligand), which is used to treat basal cell carcinoma (Urosevic et al. 2005; Panelli et al. 2007; Stary et al. 2007). . Clearly, understanding the functions of DCs in the tumor bed represents an important area of future investigation and exploitation for therapy.
An interesting strategy would be to rewire their molecular pathways from “pro-tumor” DCs to “anti-tumor” DCs. Cancer cells attract immature DC possibly through chemokines such as MIP3 alpha and/or SDF-1. The DC can then be either blocked or skewed in their maturation, for example by VEGF, leading to induction of polarized CD4+ T cells that promote the expansion of cancer cells (pro-cancer) at the expense of CD8+ T cells that can cause tumor regression (anti-cancer).
Outcomes of Current DC Vaccination Trials
The Quality of Elicited Antigen-Specific Immune Responses
Indeed, the immune responses elicited by the first generation of DC vaccines may not be of a quality to enable the rejection of bulky tumors. In addition, T cells with low avidity may be unable to recognize and/or kill peptide-MHC class I complexes on tumor cells (Appay et al. 2008). Finally, the tumor microenvironment can inhibit the functions of effector T cells, for example through the action of myeloid-derived suppressor cells and Tregs, as summarized in recent reviews (Gabrilovich and Nagaraj 2009; Menetrier-Caux et al. 2009).
Recent advances in immunomonitoring of specific immune responses in blood and at the tumor site should help us address these questions (Palucka et al. 2006; Vence et al. 2007; Butterfield et al. 2008; Janetzki et al. 2009; Tahara et al. al. 2009). Modern approaches including polychromatic flow cytometry rather than the analysis of a single cytokine (eg, IFN-gELISPOT) and/or the frequency of tetramer positive cells will contribute to a better assessment of the quality of the induced immune responses in patients (Kammula et al. .1999; Lee et al.1999). Indeed, several studies, mostly conducted in the context of HIV vaccines, have concluded that a simple measurement of the frequency of IFN-g secreting CD8+ T cells is insufficient to assess the quality of the immunity induced from the vaccine (Wille-Reece et. al.2006; Appay et al.2008; Seder et al.2008).
Optimal DCs
Studies in mice show that specific targeting of antigen to DCs in vivo results in a significant enhancement of CD4+ and CD8+ T cell antigen-specific immunity when a DC maturation signal is provided (Hawiger et al. For example, TLR2 ligation promotes the induction of Tregs instead of cells Th1 or Th17 (Manicassamy et al. 2009), does not appear to be a preferred option for cancer vaccines These pioneering studies have already been extended to demonstrate the targeting of tumor antigens to DCs (Caminschi et al. 2009) and Langerhans cells (LC) in animal models (Flacher et al. and generation of antitumor immunity (Wei et al. 2009).
Candidate tumor antigens include: (a) unique (mutated) antigens; and (b) shared self-antigens, including cancer/testis antigens and tissue differentiation antigens (Gilboa1999; Vlad et al.2004; Boon et al.2006; Parmiani et al.2007). Mutated antigens are thought to provide several benefits; for example, their specific T cell repertoire should not be removed because they are not recognized as “self” by immune cells (Parmiani et al. 2007). It has now been shown that the disease is due to the development of cdr-2-specific CD8+CTL (Albert et al. 1998).
The list of onconeural antigens is growing, and in addition to cdr2, two other antigens, Nova and amphiphysin, are emerging as potential targets of the immune system (Floyd et al. 1998; Rosin et al. 1998). An important shift in the selection of antigenic targets could be caused by the identification of cancer stem cells (Jordan et al. 2006; Polyak and Hahn 2006; Rossi et al. 2008). The importance of stem cell-associated antigens in malignancy can be best illustrated by the presence of SOX-2-specific immunity in patients with monoclonal gammopathy (Spisek et al. 2007).
So far, all antigenic targets are protein antigens whose peptides can be presented on the cell surface in the form of complexes with classical MHC molecules (Townsend et al. 1985). However, tumors express altered lipids and sugars that can be bound by CD1 molecules on APCs and presented to NKT cells as well as T cells (Beckman et al.1994; Fujii et al.2002; Hava et al.2005).
Combining DC Vaccines with Other Therapies
The discovery of onconeural antibodies led to the proposal that paraneoplastic cerebellar degeneration (PCD), associated with breast and ovarian cancer, is an autoimmune disorder mediated by the humoral arm of the immune system. These antibodies allowed the cloning of the cdr2 antigen, a protein with a helix/leucine chain domain. While most studies have focused on eliminating mature cancer cells with limited proliferative capacity, it appears more efficient to target self-renewing cancer stem cells.
Ideal target genes would be those shared by cancer cells and embryonic cells that are required for cancer cell survival but not expressed in adult stem cells (Dhodapkar 2010). In particular, antibodies or other soluble antagonists, such as modified receptors, can be used to block suppressive cytokines in the tumor microenvironment, such as IL-10 (Moore et al. 2001), IL-13 (Terabe et al. 2000). ), TGF-b (Li et al. 2005; Terabe et al. 2009) and VEGF (Gabrilovich 2004; Rabinovich et al. 2007). However, the clinical efficacy of current approaches is limited, probably because tumors invade the immune system with the help of myeloid-derived suppressor cells, type 2 inflammatory T cells, and regulatory T cells (Tregs).
