The Cooperation of IL-29 and PLGA Nanoparticles Improves the Protective Immunity of the gD-1 DNA Vaccine Against Herpes Simplex Virus Type 1 in Mice.

In clinical practice, the low immunogenicity and low stability of the DNA plasmid vaccine candidates are two significant shortcomings in their application against infectious diseases. To overcome these two disadvantages, the plasmid expressing IL-29 (pIL-29) as a genetic adjuvant and polylactic-co-glycolic acid (PLGA) as a non-viral delivery system were used, respectively. In this study, the pIL-29 encapsulated in PLGA nanoparticles (nanoIL-29) and the pgD1 encapsulated in PLGA nanoparticles (nanoVac) were simultaneously applied to boost immunologic responses against HSV-1. We generated spherical nanoparticles with encapsulation efficiency of 75 ± 5% and sustained the release of plasmids from them. Then, Balb/c mice were subcutaneously immunized twice with nanoVac+nanoIL-29, Vac+IL-29, nanoVac, Vac, nanoIL-29, and/or IL-29 in addition to negative and positive control groups. Cellular immunity was evaluated via lymphocyte proliferation assay, cytotoxicity test, and IFN-γ, IL-4, and IL-2 measurements. Mice were also challenged with 50X LD50 of HSV-1. The nanoVac+nanoIL-29 candidate vaccine efficiently enhances CTL and Th1-immune responses and increases the survival rates by 100% in mice vaccinated by co-administration of nanoVac and nanoIL-29 against the HSV-1 challenge. The newly proposed vaccine is worth studying in further clinical trials, because it could effectively improve cellular immune responses and protected mice against HSV-1.

Adar1 deletion causes degeneration of the exocrine pancreas via Mavs-dependent interferon signaling.

Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA-binding protein that deaminates adenosine (A) to inosine (I). A-to-I editing alters post-transcriptional RNA processing, making ADAR1 a crucial regulator of gene expression. Consequently, Adar1 has been implicated in organogenesis. To determine the role of Adar1 in pancreatic development and homeostasis, we conditionally deleted Adar1 from the murine pancreas (Ptf1aCre/+; Adar1Fl/Fl). The resulting mice had stunted growth, likely due to malabsorption associated with exocrine pancreatic insufficiency. Analyses of pancreata revealed ductal cell expansion, heightened interferon-stimulated gene expression and an increased influx of immune cells. Concurrent deletion of Adar1 and Mavs, a signaling protein implicated in the innate immune pathway, rescued the degenerative phenotype and resulted in normal pancreatic development. Taken together, our work suggests that the primary function of Adar1 in the pancreas is to prevent aberrant activation of the Mavs-mediated innate immune pathway, thereby maintaining pancreatic homeostasis.

Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer.

Aerobic exercise is associated with decreased cancer incidence and cancer-associated mortality. However, little is known about the effects of exercise on pancreatic ductal adenocarcinoma (PDA), a disease for which current therapeutic options are limited. Herein, we show that aerobic exercise reduces PDA tumor growth, by modulating systemic and intra-tumoral immunity. Mechanistically, exercise promotes immune mobilization and accumulation of tumor-infiltrating IL15Rα+ CD8 T cells, which are responsible for the tumor-protective effects. In clinical samples, an exercise-dependent increase of intra-tumoral CD8 T cells is also observed. Underscoring the translational potential of the interleukin (IL)-15/IL-15Rα axis, IL-15 super-agonist (NIZ985) treatment attenuates tumor growth, prolongs survival, and enhances sensitivity to chemotherapy. Finally, exercise or NIZ985 both sensitize pancreatic tumors to αPD-1, with improved anti-tumor and survival benefits. Collectively, our findings highlight the therapeutic potential of an exercise-oncology axis and identify IL-15 activation as a promising treatment strategy for this deadly disease.

T cell receptor repertoires of ex vivo-expanded tumor-infiltrating lymphocytes from breast cancer patients.

A higher level of tumor-infiltrating lymphocytes (TILs) is associated with better prognosis in breast cancer patients. Adoptive transfer of lymphocytes coupled with conventional therapies has appealed to many clinicians and investigators as an effective treatment strategy for cancer patients, which necessitates efficient activation and expansion of cytotoxic T lymphocytes precisely targeting cancer cells. To comprehensively understand composition of TILs and to provide a grounding in adoptive T cell therapy, we analyzed the T cell receptor (TCR) repertoires in ex vivo-expanded TILs from nine breast cancer patients via next-generation sequencing. For the three of them, TCR repertoires of TILs gathered after the initial culture during 2 weeks were additionally analyzed and compared to those of TILs that underwent ex vivo rapid expansion procedure (REP). Diversity of TCR repertoire was variable among the patients. V/J segment usage in the clonotypes was similar among patients, with variable distribution of read counts for each V/J segment. The top 50% of most frequently observed VJ combinations was present in > 80% of the total clonotypes. Compared with TCGA data, the samples contained a similar amount of recurrent CDR3 sequences, but clonotype expansion was variable among the samples. In terms of clinicopathologic factor, presence of in vitro reactivity among triple-negative breast cancer cases seemed to be related to lower Shannon's index, but p value was not statistically significant. In addition, the proportion of CD45RO+ cells out of CD8+ T cells were negatively correlated with Shannon's diversity index for both TCRα and TCRß chains (p = 0.010) via Spearman test. In this study, we identified a heterogeneous pattern of expanded T cell clones and stable usage of V/J segments in ex vivo-expanded TILs from breast cancer patients. Further large-scale studies are requisite to elucidate the clinical significance of TCR repertoires.