Blockade of CTLA-4 increases anti-tumor response inducing potential of dendritic cell vaccine.

The immunosuppressive state of the tumor microenvironment diminishes the efficacy of dendritic cell (DC)-based cancer immunotherapy. Inhibitory immune checkpoint molecules expressed on tumor-infiltrating T lymphocytes, such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) molecules are one of the main barriers in priming T cells by DCs. Therefore, it seems that blockade of such molecules facilitates the T cells activation by the DC vaccine. In this study, we intended to suppress the expression of CTLA-4 molecule on tumor-infiltrating T cells by siRNA-loaded chitosan-lactate (CL) nanoparticles to facilitate priming anti- tumor T cells by tumor lysate-loaded DC vaccine. Nanoparticles (NPs) have also provided an opportunity for specific drug delivery into the tumor site. CL NPs exhibited favorable physicochemical characteristics (size about 75 nm, polydispersive index<0.2, and a zeta potential about 14), which were associated with a high transfection rate and low toxicity. Moreover, the administration of anti-CTLA-4 siRNA-loaded NPs into CT26 and 4 T1 tumor -bearing mice led to the downregulation of CTLA-4 on tumor -infiltrating T cells, which was associated with tumor regression and increased mice survival. Moreover, while the treatment of tumor -bearing mice with DC vaccine had mild therapeutic outcomes, its combination with siRNA-loaded NPs may exhibit synergistic anti- tumor effects. This possible synergistic ameliorating effect is achieved through the reduction of immunosuppressive cells, the improved cytotoxicity of T lymphocytes, decreased inhibitory and increased inflammatory cytokines, and reduced angiogenesis and metastasis processes. These results indicate that the silencing of CTLA-4 can potentiate the T cell priming capacity of the DC vaccine, proposing a practical anti-cancer therapeutic approach.

Codelivery of STAT3 siRNA and BV6 by carboxymethyl dextran trimethyl chitosan nanoparticles suppresses cancer cell progression.

High expression of inhibitor of apoptosis (IAP) molecules in cancer cells promotes cancer cell chemoresistance. Use of BV6, a well-known IAP inhibitor, along with inhibition of signal transducer and activator of transcription 3 (STAT3), which is an important factor in the survival of tumor cells, and NIK as a mediator of BV6 unpredicted side effects, can induce effective apoptosis in tumor cells. The present study has investigated the combination therapy of cancer cells using Carboxymethyl Dextran-conjugated trimethyl chitosan (TMC-CMD) nanoparticles (NPs) loaded with NIK/STAT3-specific siRNA and BV6 to synergistically induce apoptosis in the breast, colorectal and melanoma cancer cell lines. Our results showed that in addition to enhanced pro-apoptotic effects, this combination therapy reduced proliferation, cell migration, colony formation, and angiogenesis, along with expression of factors including IL-10 and HIF in tumor cells. The results indicate the potential of this combination therapy for further investigation in animal models of cancer.

Regulatory T cells in breast cancer as a potent anti-cancer therapeutic target.

Despite marked advances in treatment approaches, breast cancer is still going to be more prevalent, worldwide. High levels of regulatory T (Treg) cells have repeatedly been demonstrated in circulation, lymph nodes, and tumor samples from patients with various cancer types. The transcription factor Forkhead box protein 3 (Foxp3)-expressing Treg cells have the high suppressive potential of the immune system and are fundamental in preserving immune homeostasis and self-tolerance. However, they enhance tumor development by curbing efficient anti-tumor immune mechanisms in malignancies. Moreover, the accumulation of Treg cells in breast tumors is related to the short overall survival of patients. Treg cell frequency has been applied as an independent predicting factor to diagnose patients with a high risk of relapse. Pulling out all populations of Treg cells to promote the efficacy of anticancer treatment methods may potentially lead to hazardous autoimmune disorders. Thus, realizing the exact structure of tumor-infiltrating Treg cells is pivotal to efficiently target Treg cells in tumors. There are exclusive and non-exclusive approaches to lower down and degrade the number/function of Treg cells. These approaches can include inhibiting tumoral migration, depletion, interference with function, and utilizing T cell plasticity. This review article attempts to clarify the implications concerning the involvement of Treg cells in breast cancer progression and discuss the current approaches in the treatment of this cancer via modulation of Treg cells function.

Hypoxia inducible factors in the tumor microenvironment as therapeutic targets of cancer stem cells.

Cancer stem cells (CSC) constitute a small area of the tumor mass and are characterized by self-renewal, differentiation and the ability to promote the development of secondary chemo-resistant tumors. Self-renewal of CSCs is regulated through various signaling pathways including Hedgehog, Notch, and Wnt/ß-catenin pathways. A few surface markers have been identified, which provide a means of targeting CSCs according to tumor type. Depending on the proximity of CSCs to the tumor hypoxic niche, hypoxia-inducible factors (HIFs) can play a critical role in modulating several CSC-related characteristics. For instance, the upregulation of HIF-1 and HIF-2 at tumor sites, which correlates with the expansion of CSCs and poor cancer prognosis, has been demonstrated. In this review, we will discuss the mechanisms by which hypoxia enhances the development of CSCs in the tumor microenvironment. Targeting HIFs in combination with other common therapeutics is pre-requisite for effective eradication of CSCs.