NK cells with tissue-resident traits shape response to immunotherapy by inducing adaptive antitumor immunity

T cell-directed cancer immunotherapy often fails to generate lasting tumor control. Harnessing additional effectors of the immune response against tumors may strengthen the clinical benefit of immunotherapies. Here, we demonstrate that therapeutic targeting of the interferon-γ (IFN-γ)-interleukin-12 (IL-12) pathway relies on the ability of a population of natural killer (NK) cells with tissue-resident traits to orchestrate an antitumor microenvironment. In particular, we used an engineered adenoviral platform as a tool for intratumoral IL-12 immunotherapy (AdV5-IL-12) to generate adaptive antitumor immunity. Mechanistically, we demonstrate that AdV5-IL-12 is capable of inducing the expression of CC-chemokine ligand 5 (CCL5) in CD49a+ NK cells both in tumor mouse models and tumor specimens from patients with cancer. AdV5-IL-12 imposed CCL5-induced type I conventional dendritic cell (cDC1) infiltration and thus increased DC-CD8 T cell interactions. A similar observation was made for other IFN-γ-inducing therapies such as Programmed cell death 1 (PD-1) blockade. Conversely, failure to respond to IL-12 and PD-1 blockade in tumor models with low CD49a+ CXCR6+ NK cell infiltration could be overcome by intratumoral delivery of CCL5. Thus, therapeutic efficacy depends on the abundance of NK cells with tissue-resident traits and, specifically, their capacity to produce the DC chemoattractant CCL5. Our findings reveal a barrier for T cell-focused therapies and offer mechanistic insights into how T cell-NK cell-DC cross-talk can be enhanced to promote antitumor immunity and overcome resistance

NK cells with tissue-resident traits shape response to immunotherapy by inducing adaptive antitumor immunity

T cell-directed cancer immunotherapy often fails to generate lasting tumor control. Harnessing additional effectors of the immune response against tumors may strengthen the clinical benefit of immunotherapies. Here, we demonstrate that therapeutic targeting of the interferon-γ (IFN-γ)-interleukin-12 (IL-12) pathway relies on the ability of a population of natural killer (NK) cells with tissue-resident traits to orchestrate an antitumor microenvironment. In particular, we used an engineered adenoviral platform as a tool for intratumoral IL-12 immunotherapy (AdV5-IL-12) to generate adaptive antitumor immunity. Mechanistically, we demonstrate that AdV5-IL-12 is capable of inducing the expression of CC-chemokine ligand 5 (CCL5) in CD49a; +; NK cells both in tumor mouse models and tumor specimens from patients with cancer. AdV5-IL-12 imposed CCL5-induced type I conventional dendritic cell (cDC1) infiltration and thus increased DC-CD8 T cell interactions. A similar observation was made for other IFN-γ-inducing therapies such as Programmed cell death 1 (PD-1) blockade. Conversely, failure to respond to IL-12 and PD-1 blockade in tumor models with low CD49a; +; CXCR6; +; NK cell infiltration could be overcome by intratumoral delivery of CCL5. Thus, therapeutic efficacy depends on the abundance of NK cells with tissue-resident traits and, specifically, their capacity to produce the DC chemoattractant CCL5. Our findings reveal a barrier for T cell-focused therapies and offer mechanistic insights into how T cell-NK cell-DC cross-talk can be enhanced to promote antitumor immunity and overcome resistance

Early Colonization with a Group of Lactobacilli Decreases the Risk for Allergy at Five Years of Age Despite Allergic Heredity

Background: Microbial deprivation early in life can potentially influence immune mediated disease development such as allergy. The aims of this study were to investigate the influence of parental allergy on the infant gut colonization and associations between infant gut microbiota and allergic disease at five years of age. Methods and Findings: Fecal samples were collected from 58 infants, with allergic or non-allergic parents respectively, at one and two weeks as well as at one, two and twelve months of life. DNA was extracted from the fecal samples and Real time PCR, using species-specific primers, was used for detection of Bifidobacterium (B.) adolescentis, B. breve, B. bifidum, Clostridium (C.) difficile, a group of Lactobacilli (Lactobacillus (L.) casei, L. paracasei and L. rhamnosus) as well as Staphylococcus (S.) aureus. Infants with non-allergic parents were more frequently colonized by Lactobacilli compared to infants with allergic parents (p = 0.014). However, non-allergic five-year olds acquired Lactobacilli more frequently during their first weeks of life, than their allergic counterparts, irrespectively of parental allergy (p = 0.009, p = 0.028). Further the non-allergic children were colonized with Lactobacilli on more occasions during the first two months of life (p = 0.038). Also, significantly more non-allergic children were colonized with B. bifidum at one week of age than the children allergic at five years (p = 0.048). Conclusion: In this study we show that heredity for allergy has an impact on the gut microbiota in infants but also that earl

Conformational flexibility of RNA polymerase III during transcriptional elongation

RNA polymerase (Pol) III is responsible for the transcription of genes encoding small RNAs, including tRNA, 5S rRNA and U6 RNA. Here, we report the electron cryomicroscopy structures of yeast Pol III at 9.9 Å resolution and its elongation complex at 16.5 Å resolution. Particle sub-classification reveals prominent EM densities for the two Pol III-specific subcomplexes, C31/C82/C34 and C37/C53, that can be interpreted using homology models. While the winged-helix-containing C31/C82/C34 subcomplex initiates transcription from one side of the DNA-binding cleft, the C37/C53 subcomplex accesses the transcription bubble from the opposite side of this cleft. The transcribing Pol III enzyme structure not only shows the complete incoming DNA duplex, but also reveals the exit path of newly synthesized RNA. During transcriptional elongation, the Pol III-specific subcomplexes tightly enclose the incoming DNA duplex, which likely increases processivity and provides structural insights into the conformational switch between Pol III-mediated initiation and elongation

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Lack of PPARγ in Myeloid Cells Confers Resistance to Listeria monocytogenes Infection

The peroxisomal proliferator-activated receptor γ (PPARγ) is a nuclear receptor that controls inflammation and immunity. Innate immune defense against bacterial infection appears to be compromised by PPARγ. The relevance of PPARγ in myeloid cells, that organize anti-bacterial immunity, for the outcome of immune responses against intracellular bacteria such as Listeria monocytogenes in vivo is unknown. We found that Listeria monocytogenes infection of macrophages rapidly led to increased expression of PPARγ. This prompted us to investigate whether PPARγ in myeloid cells influences innate immunity against Listeria monocytogenes infection by using transgenic mice with myeloid-cell specific ablation of PPARγ (LysMCre×PPARγflox/flox). Loss of PPARγ in myeloid cells results in enhanced innate immune defense against Listeria monocytogenes infection both, in vitro and in vivo. This increased resistance against infection was characterized by augmented levels of bactericidal factors and inflammatory cytokines: ROS, NO, IFNγ TNF IL-6 and IL-12. Moreover, myeloid cell-specific loss of PPARγ enhanced chemokine and adhesion molecule expression leading to improved recruitment of inflammatory Ly6Chi monocytes to sites of infection. Importantly, increased resistance against Listeria infection in the absence of PPARγ was not accompanied by enhanced immunopathology. Our results elucidate a yet unknown regulatory network in myeloid cells that is governed by PPARγ and restrains both listeriocidal activity and recruitment of inflammatory monocytes during Listeria infection, which may contribute to bacterial immune escape. Pharmacological interference with PPARγ activity in myeloid cells might represent a novel strategy to overcome intracellular bacterial infection

The Compton Spectrometer and Imager

The Compton Spectrometer and Imager (COSI) is a NASA Small Explorer (SMEX) satellite mission in development with a planned launch in 2027. COSI is a wide-field gamma-ray telescope designed to survey the entire sky at 0.2-5 MeV. It provides imaging, spectroscopy, and polarimetry of astrophysical sources, and its germanium detectors provide excellent energy resolution for emission line measurements. Science goals for COSI include studies of 0.511 MeV emission from antimatter annihilation in the Galaxy, mapping radioactive elements from nucleosynthesis, determining emission mechanisms and source geometries with polarization measurements, and detecting and localizing multimessenger sources. The instantaneous field of view for the germanium detectors is >25% of the sky, and they are surrounded on the sides and bottom by active shields, providing background rejection as well as allowing for detection of gamma-ray bursts and other gamma-ray flares over most of the sky. In the following, we provide an overview of the COSI mission, including the science, the technical design, and the project status.Comment: 8 page

The cosipy library: COSI's high-level analysis software

The Compton Spectrometer and Imager (COSI) is a selected Small Explorer (SMEX) mission launching in 2027. It consists of a large field-of-view Compton telescope that will probe with increased sensitivity the under-explored MeV gamma-ray sky (0.2-5 MeV). We will present the current status of cosipy, a Python library that will perform spectral and polarization fits, image deconvolution, and all high-level analysis tasks required by COSI's broad science goals: uncovering the origin of the Galactic positrons, mapping the sites of Galactic nucleosynthesis, improving our models of the jet and emission mechanism of gamma-ray bursts (GRBs) and active galactic nuclei (AGNs), and detecting and localizing gravitational wave and neutrino sources. The cosipy library builds on the experience gained during the COSI balloon campaigns and will bring the analysis of data in the Compton regime to a modern open-source likelihood-based code, capable of performing coherent joint fits with other instruments using the Multi-Mission Maximum Likelihood framework (3ML). In this contribution, we will also discuss our plans to receive feedback from the community by having yearly software releases accompanied by publicly-available data challenges

Mars’ Surface Radiation Environment Measured with the Mars Science Laboratory’s Curiosity Rover

The Radiation Assessment Detector (RAD) on the Mars Science Laboratory’s Curiosity rover began making detailed measurements of the cosmic ray and energetic particle radiation environment on the surface of Mars on 7 August 2012. We report and discuss measurements of the absorbed dose and dose equivalent from galactic cosmic rays and solar energetic particles on the Martian surface for ~300 days of observations during the current solar maximum. These measurements provide insight into the radiation hazards associated with a human mission to the surface of Mars, and provide an anchor point to model the subsurface radiation environment, with implications for microbial survival times of any possible extant or past life, as well as for the preservation of potential organic biosignatures of the ancient Martian environment