"Moreover, HCC patients with tumors containing infiltrated tumor-specific effector T cells have a reduced risk of tumor recurrence following liver transplantation . The following methods of adjuvant therapy were proposed for the treatment of HCC patients: cellular immunotherapy , interferon (IFN) therapy , and therapy using endogenous IFN inducers . It should be noted that in many cases, HCC develops on a background of chronic inflammatory liver disease such as hepatitis B and C or cirrhosis. "
[Show abstract][Hide abstract] ABSTRACT: Background
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with limited therapeutic options. Since HCC has been shown to be immunogenic, immunotherapy is considered a promising therapeutic approach. Small interfering RNAs (siRNAs), depending on their structure and sequence, can trigger the innate immune system, which can potentially enhance the adaptive anticancer immune response in the tumor-bearing subjects. Immunostimulatory properties of nucleic acids can be applied to develop adjuvants for HCC treatment.
The transplantable HCC G-29 tumor in male CBA/LacSto (CBA) mice was used to study the effects of immunostimulatory RNA on tumor growth. Tumor size, metastases area in different organs of mice and mouse survival rate were analyzed. Furthermore the mouse serum IFN-α levels were measured using ELISA.
In the present study, we found that a 19-bp RNA duplex (ImmunoStimulattory RNA or isRNA) with 3-nt overhangs at the 3′-ends of specific sequence displays immunostimulatory, antitumor, and antimetastatic activities in mice bearing HCC G-29. Our results demonstrate that isRNA strongly increases the level of interferon-α (IFN-α) by up to 25-fold relative to the level in mice injected with Lipofectamine alone (Mock), and to a lesser extent increases the level of proinflammatory cytokine interleukin-6 (IL-6) (by up to 5.5-fold relative to the Mock level), in mice blood serum. We showed that isRNA reliably (P < 0.05) inhibits primary tumor growth in mice compared to the mock group. Furthermore, injections of isRNA significantly enhanced necrotic processes in the center of the primary tumor, and decreased by twofold the width of the undifferentiated peripheral zone and the number of mitotic cells in this zone. The results showed that isRNA efficiently reduces the area of metastases in the liver, kidneys, and heart of CBA/LacSto mice with HCC.
The obtained results clearly demonstrate immunostimulatory and antimetastatic properties of the isRNAs in mice with HCC. Consequently, this short double-stranded RNA can be considered as a potential adjuvant for the therapy of HCC.
BMC Cancer 05/2014; 14(1):338. DOI:10.1186/1471-2407-14-338 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tumor-initiating cells(TICs) are a subpopulation of chemoresistant tumor cells that have been shown to cause tumor recurrence. Targeting and eliminating of TICs are therefore priorities for the development of new therapeutic paradigms. Much promise lies in adoptive immunotherapy. Cytokine-induced killer (CIK) cells are heterogeneous ex vivo-expanded T lymphocytes, with a mixed T-NK phenotype. It represents a realistic new option in the field of Hepatocellular carcinoma(HCC) immunotherapy. In the very recent years, Large clinical trials demonstrated that CIK cells could improve the Progression Free Survival (PFS) and Overall Survival(OS) in patients with HCC. By the same time, several studies reported that CIK cells were capable of clearing cells with stemness features in Lymphoma, Melanoma, Bone and Soft-Tissue Sarcomas. Based on the findings above mentioned, we hypothesized that CIK cells could eliminate the tumor-initiating cells, improving the PFS and OS of patients with HCC when combined with radiofrequency ablation(RFA) or transcatheter arterial chemoembolization(TACE).
Medical Hypotheses 08/2014; 84(3). DOI:10.1016/j.mehy.2014.08.022 · 1.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Few studies have investigated the impact of liver cirrhosis on dendritic cell function. The purpose of this study was to compare the activation and antigen-presentation capacity of monocyte-derived dendritic cells (MoDC) from cirrhotic patients (CIR) relative to healthy donors (HD). MoDC from CIR and HD were matured, phenotyped, irradiated and pulsed with 15mer peptides for two hepatocellular carcinoma-related antigens, alphafetoprotein and glypican-3, then co-cultured with autologous T-cells. Expanded T-cells were evaluated by interferon-gamma ELISPOT and intracellular staining. 15 CIR and 7 HD were studied. While CD14+ monocytes from CIR displayed enhanced M2 polarization, under MoDC-polarizing conditions, we identified no significant difference between HD and CIR in maturation-induced upregulation of co-stimulation markers. Furthermore, no significant differences were observed between CIR and HD in subsequent expansion of tumor antigen-specific IFNγ+ T-cells. Conclusion: MoDCs isolated from cirrhotic individuals retain similar capacity for in vitro activation, maturation and antigen-presentation as those from healthy donors.
Published by Elsevier Inc.
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