Immunotherapy of hepatocellular carcinoma with small double-stranded RNA

Abstract

BackgroundHepatocellular 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.MethodsThe 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.ResultsIn 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.ConclusionsThe 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.

Pathophysiology of Osteonecrosis of the Jaws

“…Tumor pathogenesis is often associated with an impaired immune function [96], and animal studies have implicated immune deficiency in the development of ONJ, while infusion of mesenchymal stem cells or T-regulatory cells prevents and alleviates ONJ-like lesions [97]. In addition, the highest prevalence of ONJ in patients with multiple myeloma, who receive steroids and anti-angiogenics as part of their chemotherapy regimen further points to a role of immune dysfunction in ONJ pathogenesis [87].…”

Development and validation of a novel immune-related prognostic model in hepatocellular carcinoma

“…CXCL12, CCL20), as the immune molecules members of immune system, also play a crucial role in HCC growth, invasion and metastasis [14,15]. It is proven that immunogenicity makes the immunotherapy of HCC a promising prospect [16]. Research progress discovery that programmed cell death-1 (PD-1) pathway is a new target for HCC immunotherapy [17].…”

CRKL knockdown promotes in vitro proliferation, migration and invasion, in vivo tumor malignancy and lymph node metastasis of murine hepatocarcinoma Hca-P cells

“…Characterized with high recurrence, metastasis and poor prognosis [5], hepatocarcinoma is one of the leading causes of cancer-related deaths [6]. Initial LNM of epithelial carcinoma commonly results in poor survival and prognosis of cancer patients [7,8]. The study of LNM helps in better management of hepatocarcinoma.…”