Vaccination with a combination of STING agonist-loaded lipid nanoparticles and CpG-ODNs protects against lung metastasis via the induction of CD11bhighCD27low memory-like NK cells.

BACKGROUND: Natural killer (NK) cells are effective in attacking tumor cells that escape T cell attack. Memory NK cells are believed to function as potent effector cells in cancer immunotherapy. However, knowledge of their induction, identification, and potential in vivo is limited. Herein, we report on the induction and identification of memory-like NK cells via the action of a combination of a stimulator of interferon genes (STING) agonist loaded into lipid nanoparticles (STING-LNPs) and cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG-ODNs), and the potential of the inducted memory-like NK cells to prevent melanoma lung metastasis. METHODS: The antitumor effects of either the STING-LNPs, CpG-ODNs, or the combination therapy were evaluated using a B16-F10 lung metastasis model. The effect of the combined treatment was evaluated by measuring cytokine production. The induction of memory-like NK cells was demonstrated via flow cytometry and confirmed through their preventative effect. RESULTS: The combination of STING-LNPs and CpG-ODNs tended to enhance the production of interleukin 12 (IL-12) and IL-18, and exerted a therapeutic effect against B16-F10 lung metastasis. The combination therapy increased the population of CD11bhighCD27low NK cells. Although monotherapies failed to show preventative effects, the combination therapy induced a surprisingly strong preventative effect, which indicates that CD11bhighCD27low cells could be a phenotype of memory-like NK cells. CONCLUSION: As far as could be ascertained, this is the first report of the in vivo induction, identification, and confirmation of a phenotype of the memory-like NK cells through a prophylactic effect via the use of an immunotherapeutic drug. Our findings provide novel insights into the in vivo induction of CD11bhighCD27low memory-like NK cells thus paving the way for the development of efficient immunotherapies.

Impact of intravenous/intranasal polyinosinic-polycytidylic acid administration on the mediastinal fat-associated lymphoid clusters and lung tissue in healthy mice.

BACKGROUND: Polyinosinic-polycytidylic acid (pIC) is a synthetic analog of double-stranded RNA. It is used as a synthetic adjuvant to induce an adaptive immune response. However, the effect of pIC on the development of mediastinal fat-associated lymphoid clusters (MFALCs) that regulate intrathoracic hemostasis has remained unidentified. METHODS: We investigated the impact of intranasal (i.n.) administration (pIC i.n. group) and intravenous (i.v.) administration (pIC i.v. group) of pIC on both MFALCs and lung tissue. RESULTS: Compared with the control phosphate-buffered saline (PBS) groups, both pIC-administered groups displayed a significant increase in the MFALC size (particularly in the pIC i.n. group), area of MFALC high endothelial venules (HEVs), area of lymphatic vessels (LVs), number of proliferating cells (particularly in the pIC i.v. group), and number of immune cells (B220+ B-lymphocytes, CD3+ T-lymphocytes, Iba1+ macrophages, and Gr-1+ granulocytes) in both MFALCs and lung tissues. In addition, a positive correlation was detected between MFALC size and proliferating cells, immune cell population, LVs, and HEVs within MFALCs in both groups. Except for the proliferating cell and B-lymphocyte populations in the i.n. administered group and granulocyte populations in both i.n. and i.v. administered routes, such correlations were significant. CONCLUSION: In all, our data indicate that local or systemic administration of pIC induces the development of MFALCs and can be used as an immunostimulant therapeutic strategy.

Interval- and cycle-dependent combined effect of STING agonist loaded lipid nanoparticles and a PD-1 antibody.

Programmed cell death 1 (PD-1) blockade combination to other drugs have attracted the interest of scientists for treating tumors resistant to PD-1 blockade. In this study, the impact of the interval, order of administration, and number of cycles of immunotherapeutic combination of stimulator of interferon genes (STING) pathway agonist loaded lipid nanoparticle (STING-LNP) and PD-1 antibody for inducing the optimal combined antitumor activity against a melanoma lung metastasis is reported. One cycle had no effect, but two and three cycles resulted in a combinedantitumor effect. The interval between the administration was found to influence the induction of the combined effect. The second and third doses increased the gene expression of the NK cell activation marker, interferon γ (IFN-γ), PD-1 and a ligand of PD-1 (PD-L1), whereas the first dose failed. NK cells in the lung showed an increase in the expression of the activation markers and PD-1 after the second dose. The combined antitumor effect of this combination therapy against melanoma lung metastasis model could be dependent on the interval as well as the number of doses of STING-LNP.These findings suggest the importance of the protocol setting when combining a nano system loaded with an immune adjuvant and PD-1 antibody.

Current strategies for different paclitaxel-loaded Nano-delivery Systems towards therapeutic applications for ovarian carcinoma: A review article.

Ovarian carcinoma (OC) is one of the leading causes of death among gynecologic malignancies all over the world. It is characterized by high mortality rate because of the lack of early diagnosis. The first-line chemotherapeutic regimen for late stage epithelial ovarian cancer is paclitaxel in combination to carboplatin. However, in most of cases, relapse occurs within six months despite the initial success of this chemotherapeutic combination. A lot of challenges have been encountered with the conventional delivery of paclitaxel in addition to the occurrence of severe off-target toxicity. One major problem is poor paclitaxel solubility which was improved by addition of Cremophor EL that unfortunately resulted in hypersensitivity side effects. Another obstacle is the multi drug resistance which is the main cause of OC recurrence. Accordingly, incorporation of paclitaxel, solely or in combination to other drugs, in nanocarrier systems has grabbed attention of many researchers to circumvent all these hurdles. The current review is the first article that provides a comprehensive overview on multi-faceted implementations of paclitaxel loaded nanoplatforms to solve delivery obstacles of paclitaxel in management of ovarian carcinoma. Moreover, challenges in physicochemical properties, biological activity and targeted delivery of PTX were depicted with corresponding solutions using nanotechnology. Different categories of nanocarriers employed were collected included lipid, protein, polymeric, solid nanoemulsion and hybrid systems. Future perspectives including imperative research considerations in ovarian cancer therapy were proposed as well.