Purpose: Oncolytic adenoviruses (Ad) represent an innovative approach to cancer therapy. Its efficacy depends on multiple actions, including direct tumor lysis and stimulation of antiviral and antitumor immune responses. In this study, we investigated the roles of T-cell responses in oncolytic adenoviral therapy.Experimental Design: An immunocompetent and viral replication-permissive Syrian hamster tumor model was used. The therapeutic mechanisms of oncolytic Ad were investigated by Tcell deletion, immunohistochemical staining, and CTL assay.Results: Deletion of T cells with an anti-CD3 antibody completely demolished the antitumor efficacy of oncolytic Ad. Intratumoral injection of Ad induced strong virus-and tumorspecific T-cell responses, as well as antiviral antibody response.Both antiviral and antitumor T-cell responses contributed to the efficacy of oncolytic Ad. Deletion of T cells increased viral replication and extended the persistence of infectious virus within tumors but almost abrogated the antitumor efficacy. Preexisting antiviral immunity promoted the clearance of injected oncolytic Ad from tumors but had no effect on antitumor efficacy. Strikingly, the repeated treatment with oncolytic Ad has strong therapeutic effect on relapsed tumors or tumors insensitive to the primary viral therapy.Conclusions: These results demonstrate that T cell-mediated immune responses outweigh the direct oncolysis in mediating antitumor efficacy of oncolytic Ad. Our data have a high impact on redesigning the regimen of oncolytic Ad for cancer treatment.

Background & Aims Liver cancer has a very dismal prognosis due to lack of effective therapy. Here, we studied the therapeutic effects of hyper-interleukin15 (hyper-IL-15), which is composed of IL-15 and the sushi domain of the IL-15 receptor α chain, on metastatic and autochthonous liver cancers. Methods Liver metastatic tumour models were established by intraportally injecting syngeneic mice with murine CT26 colon carcinoma cells or B16-OVA melanoma cells. Primary hepatocellular carcinoma (HCC) was induced by diethylnitrosamine (DEN). A hydrodynamics-based gene delivery method was used to achieve sustained hyper-IL-15 expression in the liver. Results Liver gene delivery of hyper-IL-15 robustly expanded CD8+ T and NK cells, leading to a long-term (more than 40 days) accumulation of CD8+ T cells in vivo, especially in the liver. Hyper-IL-15 treatment exerted remarkable therapeutic effects on well-established liver metastatic tumours and even on DEN-induced autochthonous HCC, and these effects were abolished by depletion of CD8+ T cells but not NK cells. Hyper-IL-15 triggered IL-12 and interferon-γ production and reduced the expression of co-inhibitory molecules on dendritic cells in the liver. Adoptive transfer of T cell receptor (TCR) transgenic OT-1 cells showed that hyper-IL-15 preferentially expanded tumour-specific CD8+ T cells and promoted their interferon-γ synthesis and cytotoxicity. Conclusions Liver delivery of hyper-IL-15 provides an effective therapy against well-established metastatic and autochthonous liver cancers in mouse models by preferentially expanding tumour-specific CD8+ T cells and promoting their anti-tumour effects.

Icariside II (ICAII) is a bioflavonoid compound which has demonstrated anti-oxidative, anti-inflammatory and anti-apoptotic biological activities. However, to the best of our knowledge, whether ICAII can alleviate myocardial ischemia and reperfusion injury (MIRI) remains unknown. The aim of the present study was to determine whether ICAII exerted a protective effect on MIRI and to investigate the potential underlying mechanism of action. A rat MIRI model was established by ligation of the left anterior descending coronary artery for 30 min, followed by a 24 h reperfusion. Pretreatment with ICAII with or without a PI3K/AKT inhibitor was administered at the beginning of reperfusion. Morphological and histological analyses were detected using hematoxylin and eosin staining; the infarct size was measured using Evans blue and 2,3,5-triphenyltetrazolium chloride staining; and plasma levels of lactate dehydrogenase (LDH) and creatine kinase-myocardial band (CK-MB) were analyzed using commercialized assay kits. In addition, the cardiac function was evaluated by echocardiography and the levels of cardiomyocyte apoptosis were determined using a TUNEL staining. The protein expression levels of Bax, Bcl-2, cleaved caspase-3, interleukin-6, tumor necrosis factor-α, PI3K, phosphorylated (p)-PI3K, AKT and p-AKT were analyzed using western blotting analysis. ICAII significantly reduced the infarct size, decreased the release of LDH and CK-MB and improved the cardiac function induced by IR injury. Moreover, ICAII pretreatment significantly inhibited myocardial apoptosis and the inflammatory response. ICAII also upregulated the expression levels of p-PI3K and p-AKT. However, the protective effects of ICAII were abolished by an inhibitor (LY294002) of the PI3K/AKT signaling pathway. In conclusion, the findings of the present study suggested that ICAII may mitigate MIRI by activating the PI3K/AKT signaling pathway.