Molecular Pathology Warren, Sarah
Journal of translational medicine,
01/2024, Letnik:
22, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Notably, immunofluorescence techniques invented by Albert Coons in 1961permitted detection of proteins in cells and tissues, 2 and in 1975, Edwin Southern invented the Southern blot to hybridize ...probes to specific DNA sequences and used the technique to identify a particular genetic polymorphism co-occurring with X-linked retinitis pigmentosa 3. Recent advances in molecular pathology, especially the development of profiling systems with higher resolution (including spatial resolution), higher plex, and ability to characterize multiple analytes from a single sample, are continuing to push the field forward. Parallel advances in statistical methods and artificial intelligence/machine learning approaches for data analysis will also drive greater biological insights and ultimately advances in patient care.
Macrophages mediate crucial innate immune responses via caspase-1-dependent processing and secretion of interleukin 1β (IL-1β) and IL-18. Although infection with wild-type Salmonella typhimurium is ...lethal to mice, we show here that a strain that persistently expresses flagellin was cleared by the cytosolic flagellin-detection pathway through the activation of caspase-1 by the NLRC4 inflammasome; however, this clearance was independent of IL-1β and IL-18. Instead, caspase-1-induced pyroptotic cell death released bacteria from macrophages and exposed the bacteria to uptake and killing by reactive oxygen species in neutrophils. Similarly, activation of caspase-1 cleared unmanipulated Legionella pneumophila and Burkholderia thailandensis by cytokine-independent mechanisms. This demonstrates that activation of caspase-1 clears intracellular bacteria in vivo independently of IL-1β and IL-18 and establishes pyroptosis as an efficient mechanism of bacterial clearance by the innate immune system.
Developing strategies to inflame tumors is critical for increasing response to immunotherapy. Here, we report that low-dose radiotherapy (LDRT) of murine tumors promotes T-cell infiltration and ...enables responsiveness to combinatorial immunotherapy in an IFN-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity and depended on both cytotoxic CD4
and CD8
T cells. LDRT elicited predominantly CD4
cells with features of exhausted effector cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, as well as a unique subset of activated dendritic cells expressing the NKG2D ligand RAE1. We translated these findings to a phase I clinical trial administering LDRT, low-dose cyclophosphamide, and immune checkpoint blockade to patients with immune-desert tumors. In responsive patients, the combinatorial treatment triggered T-cell infiltration, predominantly of CD4
cells with Th1 signatures. Our data support the rational combination of LDRT with immunotherapy for effectively treating low T cell-infiltrated tumors. SIGNIFICANCE: Low-dose radiation reprogrammed the tumor microenvironment of tumors with scarce immune infiltration and together with immunotherapy induced simultaneous mobilization of innate and adaptive immunity, predominantly CD4
effector T cells, to achieve tumor control dependent on NKG2D. The combination induced important responses in patients with metastatic immune-cold tumors.
.
The mammalian innate immune system uses Toll-like receptors (TLRs) and Nod-LRRs (NLRs) to detect microbial components during infection. Often these molecules work in concert; for example, the TLRs ...can stimulate the production of the proforms of the cytokines IL-1β and IL-18, whereas certain NLRs trigger their subsequent proteolytic processing via caspase 1. Gram-negative bacteria use type III secretion systems (T3SS) to deliver virulence factors to the cytosol of host cells, where they modulate cell physiology to favor the pathogen. We show here that NLRC4/Ipaf detects the basal body rod component of the T3SS apparatus (rod protein) from S. typhimurium (PrgJ), Burkholderia pseudomallei (BsaK), Escherichia coli (EprJ and EscI), Shigella flexneri (MxiI), and Pseudomonas aeruginosa (PscI). These rod proteins share a sequence motif that is essential for detection by NLRC4; a similar motif is found in flagellin that is also detected by NLRC4. S. typhimurium has two T3SS: Salmonella pathogenicity island-1 (SPI1), which encodes the rod protein PrgJ, and SPI2, which encodes the rod protein SsaI. Although PrgJ is detected by NLRC4, SsaI is not, and this evasion is required for virulence in mice. The detection of a conserved component of the T3SS apparatus enables innate immune responses to virulent bacteria through a single pathway, a strategy that is divergent from that used by plants in which multiple NB-LRR proteins are used to detect T3SS effectors or their effects on cells. Furthermore, the specific detection of the virulence machinery permits the discrimination between pathogenic and nonpathogenic bacteria.
Anti-PD-1 immune checkpoint blockers can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Here, we combined intravital real-time imaging ...with single-cell RNA sequencing analysis and mouse models to uncover anti-PD-1 pharmacodynamics directly within tumors. We showed that effective antitumor responses required a subset of tumor-infiltrating dendritic cells (DCs), which produced interleukin 12 (IL-12). These DCs did not bind anti-PD-1 but produced IL-12 upon sensing interferon γ (IFN-γ) that was released from neighboring T cells. In turn, DC-derived IL-12 stimulated antitumor T cell immunity. These findings suggest that full-fledged activation of antitumor T cells by anti-PD-1 is not direct, but rather involves T cell:DC crosstalk and is licensed by IFN-γ and IL-12. Furthermore, we found that activating the non-canonical NF-κB transcription factor pathway amplified IL-12-producing DCs and sensitized tumors to anti-PD-1 treatment, suggesting a therapeutic strategy to improve responses to checkpoint blockade.
Display omitted
•Effective anti-PD-1 anti-tumor responses require IL-12-producing dendritic cells•Anti-PD-1 indirectly activates IL-12 through IFN-γ produced from CD8+ T cells•Agonizing the non-canonical NF-κB pathway enhances dendritic cell IL-12 production•Combining aPD-1 with non-canonical NF-κB agonism enhances checkpoint immunotherapy
Anti-PD-1 mAbs can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Garris et al. show that effective anti-PD-1 immunotherapy requires intratumoral dendritic cells (DCs) producing IL-12. Anti-PD-1 indirectly activates DCs through IFN-γ released from drug-activated T cells. Furthermore, agonizing the non-canonical NF-κB pathway activates DCs and enhances aPD-1 therapy in an IL-12-dependent manner.
Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers
. Current predictive ...biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota
. Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8
T cells and CD20
B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8
CD20
tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7
naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy.
Purpose: Health care is advancing toward a collaborative and integrative approach that promotes general health and wellness while addressing health inequities through the consideration of broader ...social and economic factors that influence the well-being of the entire population. Recently, there has been growing evidence of public health concept applications in fields related to speech, language, and hearing. However, there is an outstanding need to explicitly define the intersection of public health, including prevention and health promotion, and the discipline of communication sciences and disorders (CSD) across the areas of education, clinical practice, research, and policy. The authors propose a definition for this intersection using the new term communication public health . Method: This tutorial provides guidance on how to conceptualize communication public health and invites refinement and expansion of the intersection between public health and CSD. Because readers are experts in CSD, this tutorial aims to supplement existing knowledge with information on public health to achieve three main objectives: (a) increase knowledge of the application of public health concepts among speech, language, hearing, and related professionals (SLHP+); (b) introduce the concept of communication public health; and (c) discuss the relevance of communication public health across domains within CSD. The authors utilize the socioecological model to provide examples of applications. Results: The concept of communication public health is proposed as the collaborative area of CSD and public health, which encompasses prevention and promotion of equity in communication health through individual-, community-, and population-level efforts. The goals of communication public health are achieved through applications of public health principles in CSD education, clinical practice, research, and policy. Conclusion: Communication public health defines an area of collaboration between public health and CSD in which SLHP+ can apply public health concepts to both advance communication health and address health disparities.
Recent studies have provided insights into the pathology of and immune response to COVID-19
. However, a thorough investigation of the interplay between infected cells and the immune system at sites ...of infection has been lacking. Here we use high-parameter imaging mass cytometry
that targets the expression of 36 proteins to investigate the cellular composition and spatial architecture of acute lung injury in humans (including injuries derived from SARS-CoV-2 infection) at single-cell resolution. These spatially resolved single-cell data unravel the disordered structure of the infected and injured lung, alongside the distribution of extensive immune infiltration. Neutrophil and macrophage infiltration are hallmarks of bacterial pneumonia and COVID-19, respectively. We provide evidence that SARS-CoV-2 infects predominantly alveolar epithelial cells and induces a localized hyperinflammatory cell state that is associated with lung damage. We leverage the temporal range of fatal outcomes of COVID-19 in relation to the onset of symptoms, which reveals increased macrophage extravasation and increased numbers of mesenchymal cells and fibroblasts concomitant with increased proximity between these cell types as the disease progresses-possibly as a result of attempts to repair the damaged lung tissue. Our data enable us to develop a biologically interpretable landscape of lung pathology from a structural, immunological and clinical standpoint. We use this landscape to characterize the pathophysiology of the human lung from its macroscopic presentation to the single-cell level, which provides an important basis for understanding COVID-19 and lung pathology in general.
PDF
