Improved antitumor effectiveness of oncolytic HSV-1 viruses engineered with IL-15/IL-15Rα complex combined with oncolytic HSV-1-aPD1 targets colon cancer.

Oncolytic virotherapy is emerging as a promising therapeutic avenue for cancer treatment, harnessing both innate and tumor-specific immune responses for targeted tumor elimination. In this study, we present a novel oncolytic virus (oHSV1-IL15B) derived from herpes simplex virus-1 (HSV-1), armed with IL-15/IL-15Rα complex, with a focus on treating colon cancer combined with oncolytic HSV-1 expressing anti-PD-1 antibody (oHSV1-aPD1). Results from our study reveal that recombinant oHSV-1 virus equipped with IL-15/IL-15Rα complex exhibited significant anti-tumor effects in a murine CT26 colon adenocarcinoma model. Notably, oHSV1-IL15B combined with oHSV-1-aPD1 demonstrates superior tumor inhibition and prolonged overall survival compared to oHSV1-mock and monotherapy groups. Further exploration highlights the impact of oHSV1-IL15B, oHSV-1-aPD1 and combined group on antitumor capacity, revealing a substantial increase in CD8+ T and CD4+ T cell proportions of CT26-bearing BALB/c mice and promoting apoptosis in tumor tissue. The study emphasizes the pivotal role of cytotoxic CD8+T cells in oncolytic virotherapy, demonstrating that recombinant oHSV1-IL15B combined with oncolytic HSV-1-aPD1 induces a robust tumor-specific T cell response. RNA sequence analysis highlighted oHSV1-IL15B combined with oHSV1-aPD1 improved tumors immune microenvironment on immune response, antiviral response-related genes and apoptosis-related genes, which contributed to anti-tumor immunotherapy. The findings underscore the promising antitumor activity achieved through the combination of IL-15/IL-15Rα complex and anti-PD-1 antibody with oHSV-1. This research opens avenues for diverse therapeutic strategies, suggesting the potential of synergistically utilizing cytokines and anti-PD-1 antibody with oncolytic viruses to enhance immunotherapy for cancer management.

The Oncolytic virus VT1092M and an Anti-PD-L1 antibody synergize to induce systemic antitumor immunity in a murine bilateral tumor model.

This study investigated the synergistic potential of an oncolytic herpes simplex virus armed with interleukin 12 (VT1092M) in combination with immune checkpoint inhibitors for enhancing antitumor responses. The potential of this combination treatment to induce systemic antitumor immunity was assessed using bilateral subcutaneous tumor and tumor re-challenge mouse models. The antitumor efficacy of various OV and ICI treatment combinations and the underlying mechanisms were explored through diverse analytical techniques, including flow cytometry and RNA sequencing. Using VT1092M, either alone or in combination with an anti-PD-L1 antibody, significantly reduced the sizes of both the injected and untreated abscopal tumors in a bilateral tumor mouse model. The combination therapy demonstrated superior antitumor efficacy to the other treatment conditions tested, which was accompanied by an increase in T cell numbers and CD8+T cell activation. Results from the survival and tumor re-challenge experiments showed that the combination therapy elicited long-term, tumor-specific immune responses, which were associated with tumor clearance and prolonged survival. Immune cell depletion assays identified CD8+T cells as the crucial mediators of systemic antitumor immunity during combination therapy. In conclusion, the combination of VT1092M and PD-L1 blockade emerged as a potent inducer of antitumor immune responses, surpassing the efficacy of each monotherapy. This synergistic approach holds promise for achieving robust and sustained antitumor immunity, with potential implications for preventing tumor metastasis in patients with cancer.

C1q/TNF-related protein 9 improves the anti-contractile effects of perivascular adipose tissue via the AMPK-eNOS pathway in diet-induced obese mice.

The anti-contractile property of perivascular adipose tissue (PVAT) is abolished through an endothelium-dependent pathway in obesity. C1q/tumor necrosis factor-related protein (CTRP)9 improved endothelial function by promoting endothelium-dependent vasodilatation. The aims of this study were to investigate whether CTRP9 improves the anti-contractile effect of PVAT and protects against PVAT dysfunction in obese mice. The mice were treated with a high-fat diet with or without CTRP9 treatment. Thoracic aortas with or without PVAT (PVAT+ or PVAT-) were prepared, and concentration-dependent responses to phenylephrine were measured. Obese mice showed a significantly increased contractile response, which was suppressed by CTRP9 treatment both with and without PVAT. PVAT significantly reduced the anti-contractile effect in obese mice, which was partially restored by CTRP9 treatment. Treatment of the aortic rings (PVAT+) with inhibitors of AMP protein kinase (AMPK), Akt and endothelial nitric oxide synthase (eNOS) attenuated the beneficial effect of CTRP9 on PVAT. Similar results were observed when we pretreated the aortic rings with CTRP9 ex vivo. CTRP9 significantly enhanced the phosphorylation levels of AMPK, Akt and eNOS, and reduced superoxide production and TNF-α levels in PVAT from obese mice. Our study suggests that CTRP9 enhanced the anti-contractile effect of PVAT and improved PVAT function by activating the AMPK-eNOS pathway in obese mice.