bims-traimu 2023-04-23 papers

Issue of 2023‒04‒23
seven papers selected by
Yantong Wan
Southern Medical University

J Immunother Cancer. 2023 Apr;pii: e006221. [Epub ahead of print]11(4):

Irreversible electroporation augments β-glucan induced trained innate immunity for the treatment of pancreatic ductal adenocarcinoma.

Matthew R Woeste, Rejeena Shrestha, Anne E Geller, Shu Li, Diego Montoya-Durango, Chuanlin Ding, Xiaoling Hu, Hong Li, Aaron Puckett, Robert A Mitchell, Traci Hayat, Min Tan, Yan Li, Kelly M McMasters, Robert C G Martin, Jun Yan.

BACKGROUND: Pancreatic cancer (PC) is a challenging diagnosis that is yet to benefit from the advancements in immuno-oncologic treatments. Irreversible electroporation (IRE), a non-thermal method of tumor ablation, is used in treatment of select patients with locally-advanced unresectable PC and has potentiated the effect of certain immunotherapies. Yeast-derived particulate β-glucan induces trained innate immunity and successfully reduces murine PC tumor burden. This study tests the hypothesis that IRE may augment β-glucan induced trained immunity in the treatment of PC.METHODS: β-Glucan-trained pancreatic myeloid cells were evaluated ex vivo for trained responses and antitumor function after exposure to ablated and unablated tumor-conditioned media. β-Glucan and IRE combination therapy was tested in an orthotopic murine PC model in wild-type and Rag-/- mice. Tumor immune phenotypes were assessed by flow cytometry. Effect of oral β-glucan in the murine pancreas was evaluated and used in combination with IRE to treat PC. The peripheral blood of patients with PC taking oral β-glucan after IRE was evaluated by mass cytometry.
RESULTS: IRE-ablated tumor cells elicited a potent trained response ex vivo and augmented antitumor functionality. In vivo, β-glucan in combination with IRE reduced local and distant tumor burden prolonging survival in a murine orthotopic PC model. This combination augmented immune cell infiltration to the PC tumor microenvironment and potentiated the trained response from tumor-infiltrating myeloid cells. The antitumor effect of this dual therapy occurred independent of the adaptive immune response. Further, orally administered β-glucan was identified as an alternative route to induce trained immunity in the murine pancreas and prolonged PC survival in combination with IRE. β-Glucan in vitro treatment also induced trained immunity in peripheral blood monocytes obtained from patients with treatment-naïve PC. Finally, orally administered β-glucan was found to significantly alter the innate cell landscape within the peripheral blood of five patients with stage III locally-advanced PC who had undergone IRE.
CONCLUSIONS: These data highlight a relevant and novel application of trained immunity within the setting of surgical ablation that may stand to benefit patients with PC.

Keywords: Immunity, Innate; Immunotherapy; Phagocytosis; Tumor Microenvironment

DOI: https://doi.org/10.1136/jitc-2022-006221

Antioxid Redox Signal. 2023 Apr 21.

Modulation of innate immune memory dynamics by subcellular ROS.

Shuo Geng, RuiCi Lin, Yajun Wu, Jing Wang, Liwu Li.

SIGNIFICANCE: Innate immune cells adopt distinct memory states during the pathogenesis of acute and chronic inflammatory diseases. Intracellular generations of reactive oxygen species (ROS) play key roles during the programming dynamics of innate immune cells such as monocytes and macrophages.RECENT ADVANCES: ROS modulates the adaptation of innate leukocytes to varying intensities and durations of inflammatory signals, facilitates fundamental reprogramming dynamics such as priming, tolerance and exhaustion, in addition to fundamental processes of proliferation, differentiation, phagocytosis, chemotaxis, as well as expression of pro- and anti-inflammatory mediators. ROS can be generated at distinct subcellular compartments including cellular membrane, mitochondria, and peroxisome. Complex inflammatory signals may finely regulate ROS generation within distinct subcellular compartments which in turn may differentially facilitate innate memory dynamics.
CRITICAL ISSUES: Complex inflammatory signals with varying strength and durations may differentially trigger ROS generation at peroxisome, mitochondria and other subcellular organelles. Peroxisomal or mitochondrial ROS may facilitate the assembly of distinct signaling platforms involved in the programming of memory innate leukocytes. Despite the emerging connection of subcellular ROS with innate immune memory, underlying mechanisms are still not well defined.
FUTURE DIRECTIONS: Recent important discoveries linking subcellular ROS and innate memory as critically reviewed here hold novel translational relevance related to acute and chronic inflammatory diseases. Capitalizing on these novel findings, future systems studies that employ next-gen single cell dynamics analyses in response to complex inflammatory environments are urgently needed in order to comprehensively decipher the programming dynamics of innate immune memory, finely modulated by subcellular ROS.

DOI: https://doi.org/10.1089/ars.2023.0304

Front Immunol. 2023 ;14 1149015

Shaping of the alveolar landscape by respiratory infections and long-term consequences for lung immunity.

Lucia Rodriguez-Rodriguez, Laurent Gillet, Bénédicte Machiels.

Respiratory infections and especially viral infections, along with other extrinsic environmental factors, have been shown to profoundly affect macrophage populations in the lung. In particular, alveolar macrophages (AMs) are important sentinels during respiratory infections and their disappearance opens a niche for recruited monocytes (MOs) to differentiate into resident macrophages. Although this topic is still the focus of intense debate, the phenotype and function of AMs that recolonize the niche after an inflammatory insult, such as an infection, appear to be dictated in part by their origin, but also by local and/or systemic changes that may be imprinted at the epigenetic level. Phenotypic alterations following respiratory infections have the potential to shape lung immunity for the long-term, leading to beneficial responses such as protection against allergic airway inflammation or against other infections, but also to detrimental responses when associated with the development of immunopathologies. This review reports the persistence of virus-induced functional alterations in lung macrophages, and discusses the importance of this imprinting in explaining inter-individual and lifetime immune variation.

Keywords: AM ontogeny; alveolar macrophages; lung immunity; niche imprinting; respiratory viruses; trained immunity

DOI: https://doi.org/10.3389/fimmu.2023.1149015

Drug Saf. 2023 Apr 19.

Implications of Non-Specific Effects for Testing, Approving, and Regulating Vaccines.

Christine Stabell Benn, Nelly Amenyogbe, Anders Björkman, Jorge Domínguez-Andrés, Eleanor N Fish, Katie L Flanagan, Sabra L Klein, Tobias R Kollmann, Kirsten Ohm Kyvik, Mihai G Netea, Naja Hulvej Rod, Frederik Schaltz-Buchholzer, Frank Shann, Liisa Selin, Sanne M Thysen, Peter Aaby.

The current framework for testing and regulating vaccines was established before the realization that vaccines, in addition to their effect against the vaccine-specific disease, may also have "non-specific effects" affecting the risk of unrelated diseases. Accumulating evidence from epidemiological studies shows that vaccines in some situations can affect all-cause mortality and morbidity in ways that are not explained by the prevention of the vaccine-targeted disease. Live attenuated vaccines have sometimes been associated with decreases in mortality and morbidity that are greater than anticipated. In contrast, some non-live vaccines have in certain contexts been associated with increases in all-cause mortality and morbidity. The non-specific effects are often greater for female than male individuals. Immunological studies have provided several mechanisms that explain how vaccines might modulate the immune response to unrelated pathogens, such as through trained innate immunity, emergency granulopoiesis, and heterologous T-cell immunity. These insights suggest that the framework for the testing, approving, and regulating vaccines needs to be updated to accommodate non-specific effects. Currently, non-specific effects are not routinely captured in phase I-III clinical trials or in the post-licensure safety surveillance. For instance, an infection with Streptococcus pneumoniae occurring months after a diphtheria-tetanus-pertussis vaccination would not be considered an effect of the vaccination, although evidence indicates it might well be for female individuals. Here, as a starting point for discussion, we propose a new framework that considers the non-specific effects of vaccines in both phase III trials and post-licensure.

DOI: https://doi.org/10.1007/s40264-023-01295-3

Innate Immun. 2023 Apr 21. 17534259231168725

A TLR4 agonist liposome formulation effectively stimulates innate immunity and enhances protection from bacterial infection.

Jodi F Hedges, Deann T Snyder, Amanda Robison, Macy A Thompson, Klara Aspelin, Jack Plewa, Jory Baldridge, Mark A Jutila.

Stimulation of innate immunity can protect against infectious insult and could be used in combination with other therapies. Since antibiotic resistance is an increasing concern, strategies to reduce the dose or eliminate the need for these drugs are warranted. Lipo-CRX is a formulation in which the TLR4 agonist CRX-527 is incorporated into lipid membranes in liposomes. Lipo-CRX is less inflammatory than either CRX-527 or LPS, but retains unique capacity to enhance host defense responses. We compared lipo-CRX to other agonists in vitro using mammalian cells and in vivo in mice, and assessed indicators of innate immune responses and protection from bacterial infection. Lipo-CRX is similar to E. coli LPS in its capacity to activate bovine γδ T cells and to recruit neutrophils into mouse lungs, but with less reactivity in the LAL assay. However, lipo-CRX uniquely induced the production of systemic innate immune cytokines. In the mouse model of brucellosis, delivery of lipo-CRX to the lungs reduced the dissemination of B. abortus. While lipo-CRX or the antibiotic ampicillin alone did not alter B. abortus burdens in the lung, the combination had a synergistic beneficial effect. Our data suggest that stimulating the innate immune system with lipo-CRX, either alone or when combined with antibiotics, can enhance bacterial clearance in the mouse model of brucellosis.

Keywords: Adjuvant; Brucella; antibiotics; brucellosis; innate immunity

DOI: https://doi.org/10.1177/17534259231168725

Front Immunol. 2023 ;14 1046374

Staphylococcus aureus induces tolerance in human monocytes accompanied with expression changes of cell surface markers.

Mario M Müller, Christian Baldauf, Stella Hornischer, Tilman E Klassert, Antony Schneegans, Andrea Behnert, Mathias W Pletz, Stefan Hagel, Hortense Slevogt.

Exposure of human monocytes to lipopolysaccharide (LPS) or other pathogen-associated molecular pattern (PAMPs) induces a temporary insensitivity to subsequent LPS challenges, a cellular state called endotoxin tolerance (ET), associated with the pathogenesis of sepsis. In this study, we aimed to characterize the cellular state of human monocytes from healthy donors stimulated with Staphylococcus aureus in comparison to TLR2-specific ligands. We analyzed S. aureus induced gene expression changes after 2 and 24 hours by amplicon sequencing (RNA-AmpliSeq) and compared the pro-inflammatory response after 2 hours with the response in re-stimulation experiments. In parallel, glycoprotein expression changes in human monocytes after 24 hours of S. aureus stimulation were analyzed by proteomics and compared to stimulation experiments with TLR2 ligands Malp-2 and Pam3Cys and TLR4 ligand LPS. Finally, we analyzed peripheral blood monocytes of patients with S. aureus bloodstream infection for their ex vivo inflammatory responses towards S. aureus stimulation and their glycoprotein expression profiles. Our results demonstrate that monocytes from healthy donors stimulated with S. aureus and TLR ligands of Gram-positive bacteria entered the tolerant cell state after activation similar to LPS treatment. In particular reduced gene expression of pro-inflammatory cytokines (TNF, IL1β) and chemokines (CCL20, CCL3, CCL4, CXCL2, CXCL3 and CXCL8) could be demonstrated. Glycoprotein expression changes in monocytes tolerized by the different TLR agonists were highly similar while S. aureus-stimulated monocytes shared some of the PAMP-induced changes but also exhibited a distinct expression profile. 11 glycoproteins (CD44, CD274, DSC2, ICAM1, LAMP3, LILRB1, PTGS2, SLC1A3, CR1, FGL2, and HP) were similarly up- or downregulated in all four comparisons in the tolerant cell state. Monocytes from patients with S. aureus bacteremia revealed preserved pro-inflammatory responsiveness to S. aureus stimulation ex vivo, expressed increased CD44 mRNA but no other glycoprotein of the tolerance signature was differentially expressed.

Keywords: S. aureus; bacteremia; glycoproteins; marker of tolerance; membrane proteins; monocyte; proteomics; tolerance

DOI: https://doi.org/10.3389/fimmu.2023.1046374