Silencing IDO in dendritic cells: A novel approach to enhance cancer immunotherapy in a murine breast cancer model

Abstract

Cancer immunotherapeutic agents (vaccines) in the form of antigen-loaded dendritic cells (DCs) reached an important milestone with the recent approval of Provenge, the first DC vaccine for treatment of prostate cancer. Although this heralds a new era of tumor immunotherapy, it also highlights the compelling need to optimize such DC-based therapies as they are increasingly tested and used to treat human patients. In this study we sought to augment and enhance the antitumor activity of a DC-based vaccine using siRNA to silence expression of immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) in DCs. We report here that DCs loaded with tumor antigens, but with siRNA-silenced IDO expression, were introduced into 4T1 breast tumorbearing mice, the treatment: (i) lengthened the time required for tumor onset, (ii) decreased tumor size compared to tumors grown for equal lengths of time in mice treated with antigen-loaded DCs without IDO silencing and (iii) reduced CD4 1 and CD8 1 T cell apoptosis. Furthermore, immunization with IDO-silenced DCs enhanced tumor antigen-specific T cell proliferation and CTL activity, and decreased numbers of CD4 1 CD25 1 Foxp3 1 T reg . This study provides evidence to support silencing of immunosuppressive genes (IDO) as an effective strategy to enhance the efficacy of DC-based cancer immunotherapeutic.

Nanoparticle Adjuvant Sensing by TLR7 Enhances CD8+ T Cell–Mediated Protection from Listeria Monocytogenes Infection

“…In particular, VLPs loaded with CpG oligodeoxynucleotides (TLR9 ligands) have shown a very promising therapeutic potential against cancer (57,58) but also in other context such as allergen-specific immunotherapy (59)(60)(61). Cancer immunotherapy with DC-based vaccines also has provided great promises in the past few years but requires optimization to become fully effective (62,63). Our results demonstrate that PapMV is a suitable adjuvant for BMDC-based vaccines that could be applicable to the development of improved therapeutic DC vaccination strategies against cancer and chronic infections.…”

Fast dendritic cells matured with Poly (I:C) may acquire tolerogenic properties

“…Some of them, such as ILT-3, have the immunoreceptor tyrosine inhibitory motif (ITIM) [5]. Besides, IDO-1emediated degradation of tryptophan and synthesis of kynurenine by DCs was described as a crucial factor in humans that contributes to the induction of Tregs and peripheral tolerance [6]. We showed recently that the tolerogenic ILT-3 þ IDO-1 þ DCs, induced by mesenchymal stromal cells, are able to induce functional CD4 þ CD25 þ FoxP3 þ IL-10 þ Tregs and that the blockage of ILT-3 and IDO-1 in DCs abrogated that effect [7].…”

“…Additionally, activated DCs secrete an array of cytokines such as interleukin (IL)-12 [2], IL-10 [1] and IL-23 [3], which are crucial for the polarization of T-cell differentiation toward Th1, Th2 [4] or Th17 [3], respectively. Recent data show that the tolerogenic DCs express inhibitory molecules such as immunoglobulin-like transcript (ILT)-3 [5] and indolamine dioxigenase (IDO)-1 [6], which enables them to induce Tregs [7]. Whereas Th1-and Th17-mediated immune response is desirable for a successful immunotherapy of cancer, Th2-and Treg-mediated immune response can be harmful for such a therapy [8].…”

Dual activation of Toll-like receptors 7 and 9 impairs the efficacy of antitumor vaccines in murine models of metastatic breast cancer

“…In line with this, we show here that CpG upregulated the expression of IDO mRNA in DCs and that blockade of IDO improved CpG-mediated maturation of DCs in vitro, suggesting that IDO inhibition could result in more efficient antitumor DC vaccines. In fact, IDO silencing using siRNA improved the ability of tumor antigen-loaded DC vaccines to induce antitumor immunity in murine models of cancer (Zheng et al 2013) and in patients with gynecological cancer (Sioud et al 2013). It is important to highlight that NOS and IDO blockade did not rescue the maturation of CpG + R848-DCs.…”