Physicochemical and structural insights into lyophilized mRNA-LNP from lyoprotectant and buffer screenings.

The surge in RNA therapeutics has revolutionized treatments for infectious diseases like COVID-19 and shows the potential to expand into other therapeutic areas. However, the typical requirement for ultra-cold storage of mRNA-LNP formulations poses significant logistical challenges for global distribution. Lyophilization serves as a potential strategy to extend mRNA-LNP stability while eliminating the need for ultra-cold supply chain logistics.

Nucleotide modifications enable rational design of TLR7-selective ligands by blocking RNase cleavage.

Toll-like receptors 7 (TLR7) and 8 (TLR8) each sense single-stranded RNA (ssRNA), but their activation results in different immune activation profiles. Attempts to selectively target either TLR7 or TLR8 have been hindered by their high degree of homology. However, recent studies revealed that TLR7 and TLR8 bind different ligands resulting from the processing of ssRNA by endolysosomal RNases.

An Engineered IL15 Cytokine Mutein Fused to an Anti-PD1 Improves Intratumoral T-cell Function and Antitumor Immunity.

The use of cytokines for immunotherapy shows clinical efficacy but is frequently accompanied by severe adverse events caused by excessive and systemic immune activation. Here, we set out to address these challenges by engineering a fusion protein of a single, potency-reduced, IL15 mutein and a PD1-specific antibody (anti-PD1-IL15m). This immunocytokine was designed to deliver PD1-mediated, avidity-driven IL2/15 receptor stimulation to PD1 tumor-infiltrating lymphocytes (TIL) while minimally affecting circulating peripheral natural killer (NK) cells and T cells.

A GWAS approach identifies Dapp1 as a determinant of air pollution-induced airway hyperreactivity.

Asthma is a chronic inflammatory disease of the airways with contributions from genes, environmental exposures, and their interactions. While genome-wide association studies (GWAS) in humans have identified ~200 susceptibility loci, the genetic factors that modulate risk of asthma through gene-environment (GxE) interactions remain poorly understood. Using the Hybrid Mouse Diversity Panel (HMDP), we sought to identify the genetic determinants of airway hyperreactivity (AHR) in response to diesel exhaust particles (DEP), a model traffic-related air pollutant.

Exploiting MCL1 Dependency with Combination MEK + MCL1 Inhibitors Leads to Induction of Apoptosis and Tumor Regression in -Mutant Non-Small Cell Lung Cancer.

BH3 mimetic drugs, which inhibit prosurvival BCL2 family proteins, have limited single-agent activity in solid tumor models. The potential of BH3 mimetics for these cancers may depend on their ability to potentiate the apoptotic response to chemotherapy and targeted therapies. Using a novel class of potent and selective MCL1 inhibitors, we demonstrate that concurrent MEK + MCL1 inhibition induces apoptosis and tumor regression in -mutant non-small cell lung cancer (NSCLC) models, which respond poorly to MEK inhibition alone.

Type 2 innate lymphoid cell suppression by regulatory T cells attenuates airway hyperreactivity and requires inducible T-cell costimulator-inducible T-cell costimulator ligand interaction.

Background: Atopic diseases, including asthma, exacerbate type 2 immune responses and involve a number of immune cell types, including regulatory T (Treg) cells and the emerging type 2 innate lymphoid cells (ILC2s). Although ILC2s are potent producers of type 2 cytokines, the regulation of ILC2 activation and function is not well understood.

Objective: In the present study, for the first time, we evaluate how Treg cells interact with pulmonary ILC2s and control their function.

ICOS:ICOS-ligand interaction is required for type 2 innate lymphoid cell function, homeostasis, and induction of airway hyperreactivity.

Allergic asthma is caused by Th2-cell-type cytokines in response to allergen exposure. Type 2 innate lymphoid cells (ILC2s) are a newly identified subset of immune cells that, along with Th2 cells, contribute to the pathogenesis of asthma by producing copious amounts of IL-5 and IL-13, which cause eosinophilia and airway hyperreactivity (AHR), a cardinal feature of asthma. ILC2s express ICOS, a T cell costimulatory molecule with a currently unknown function.

Deficiency in the nuclear-related factor erythroid 2 transcription factor (Nrf1) leads to genetic instability.

Nuclear factor erythroid-derived 2-related factor 1 (Nrf1) regulates cellular stress response genes, and has also been suggested to play a role in other cellular processes. We previously demonstrated that hepatocyte-specific deletion of Nrf1 in mice resulted in spontaneous apoptosis, inflammation, and development of liver tumors. Here, we showed that both fibroblasts derived from Nrf1 null mouse embryos and fibroblasts expressing a conditional Nrf1 allele showed increased micronuclei and formation of abnormal nuclei.