Los modelos murinos genéticamente definidos son valiosos para investigar la resistencia/susceptibilidad a las parasitosis. Las infecciones intestinales por gusanos suelen causar una fuerte respuesta ...inmune del huésped. Aunque se acepta que el control genético de la carga parasitaria (CP) es poligénico y que la respuesta inmune está regulada en parte por genes receptores de interleucina, estudios recientes han enfatizado que los genes del complejo mayor de histocompatibilidad (CMH; H2 en ratón) desempeñan también un papel fundamental. Su variación se ha implicado como determinante de la respuesta del hospedero a parásitos gastrointestinales. El objetivo de este trabajo fue comprobar si dos líneas endocriadas de ratones de la colonia CBi-IGE (CBi/L y CBi+) que discrepan en su respuesta al desafío con dosis crecientes del nematodo T. spiralis difieren en los haplotipos H2. El ADN genómico se preparó a partir de trozos de cola de ratón mediante el método SDSproteinasa K. La tipificación de los haplotipos CMH murinos se realizó por amplificación con PCR de un corto tramo de ADN con un microsatélite altamente polimórfico del gen Eb de clase II. El genotipo CBi/L, resistente, caracterizado por tener una CP muy baja y respuesta inmune orientada hacia Th2, protectora para el hospedero, mostró un haplotipo heterocigota H2p/j. CBi+, susceptible, con CP más alta que CBi/L (p<0,0001) y tendencia a una respuesta tipo Th1 en todas las etapas del ciclo del parásito, tuvo un haplotipo H2b/j. Este resultado podría explicar, en parte, la distinta resistencia a la infección con el parásito.
Type 1 IFNs (IFN-I) generally protect mammalian hosts from virus infections, but in some cases, IFN-I is pathogenic. Because IFN-I is protective, it is commonly used to treat virus infections for ...which no specific approved drug or vaccine is available. The Middle East respiratory syndrome-coronavirus (MERS-CoV) is such an infection, yet little is known about the role of IFN-I in this setting. Here, we show that IFN-I signaling is protective during MERS-CoV infection. Blocking IFN-I signaling resulted in delayed virus clearance, enhanced neutrophil infiltration, and impaired MERS-CoV-specific T cell responses. Notably, IFN-I administration within 1 day after infection (before virus titers peak) protected mice from lethal infection, despite a decrease in IFN-stimulated gene (ISG) and inflammatory cytokine gene expression. In contrast, delayed IFN-β treatment failed to effectively inhibit virus replication, increased infiltration and activation of monocytes, macrophages, and neutrophils in the lungs, and enhanced proinflammatory cytokine expression, resulting in fatal pneumonia in an otherwise sublethal infection. Together, these results suggest that the relative timing of the IFN-I response and maximal virus replication is key in determining outcomes, at least in infected mice. By extension, IFN-αβ or combination therapy may need to be used cautiously to treat viral infections in clinical settings.
Zusammenfassung
Dupilumab greift in die Signalwege von IL‐4 und IL‐13 ein und wird erfolgreich zur Behandlung der atopischen Dermatitis eingesetzt. Genodermatosen wie das Netherton‐Syndrom, die ...Epidermolysis bullosa pruriginosa und das Hyper‐IgE‐Syndrom sind Th2‐vermittelte Erkrankungen mit Aktivierung einer Typ‐2‐Entzündung. In dieser systematischen Übersicht haben wir die therapeutische Rolle von Dupilumab bei der Behandlung von Genodermatosen untersucht. Dazu wurden die Datenbanken PubMed, Embase, Web of Science und Cochrane seit ihrer Einführung bis zum 13. Dezember 2021 systematisch durchsucht. Die Übersicht umfasst Studien mit relevanten Begriffen, einschließlich „Dupilumab“, „Genodermatose“, „Netherton‐Syndrom“, „Ichthyose“, „Epidermolysis bullosa“ und „Hyper‐IgE‐Syndrom“. Die anfängliche Suche ergab 2888 Treffer; davon wurden 28 Studien und 37 Patienten mit Genodermatosen eingeschlossen. Zu den beurteilten Genodermatosen gehörten Netherton‐Syndrom, Epidermolysis bullosa pruriginosa, Hyper‐IgE‐Syndrom, Morbus Hailey‐Hailey und schwere Ekzeme im Zusammenhang mit genetischen Erkrankungen. Die meisten der beschriebenen Fälle zeigten eine signifikante klinische Verbesserung nach Einleitung der Dupilumab‐Behandlung ohne wesentliche unerwünschte Ereignisse. Zudem wurden eine Verringerung der Immunglobulin‐E‐Spiegel und eine Normalisierung der Zytokinspiegel dokumentiert. Zusammenfassend hat Dupilumab möglicherweise eine therapeutische Rolle bei bestimmten Genodermatosen mit einer abnormal gesteigerten Typ‐2‐T‐Helfer‐Immunität (Th2), einschließlich Netherton‐Syndrom, Epidermolysis bullosa pruriginosa, Hyper‐IgE‐Syndrom, Morbus Hailey‐Hailey und schweren Ekzemen bei genetischen Erkrankungen.
HER2-positive breast cancers usually contain large amounts of T-cell infiltrate. We hypothesised that trastuzumab resistance in HER2-positive breast cancer could be mediated by immune mechanisms. We ...assessed the safety and anti-tumour activity of pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, added to trastuzumab in trastuzumab-resistant, advanced HER2-positive breast cancer.
We did this single-arm, multicentre, phase 1b–2 trial in 11 centres based in five countries. Eligible participants were women aged 18 years or older, who had advanced, histologically confirmed, HER2-positive breast cancer; documented progression during previous trastuzumab-based therapy; an Eastern Cooperative Oncology Group performance status of 0 or 1; and a formalin-fixed, paraffin-embedded metastatic tumour biopsy for central assessment of programmed cell death 1 ligand 1 (PD-L1) status. In phase 1b, we enrolled patients with PD-L1-positive tumours in a 3 + 3 dose-escalation of intravenous pembrolizumab (2 mg/kg and 10 mg/kg, every 3 weeks) plus 6 mg/kg of intravenous trastuzumab. The primary endpoint of the phase 1b study was the incidence of dose-limiting toxicity and recommended phase 2 dose; however, a protocol amendment on Aug 28, 2015, stipulated a flat dose of pembrolizumab of 200 mg every 3 weeks in all Merck-sponsored trials. In phase 2, patients with PD-L1-positive and PD-L1-negative tumours were enrolled in parallel cohorts and received the flat dose of pembrolizumab plus standard trastuzumab. The primary endpoint of the phase 2 study was the proportion of PD-L1-positive patients achieving an objective response. This trial is registered in ClinicalTrials.gov, number NCT02129556, and with EudraCT, number 2013-004770-10, and is closed.
Between Feb 2, 2015, and April 5, 2017, six patients were enrolled in phase 1b (n=3 received 2 mg/kg pembrolizumab, n=3 received 10 mg/kg pembrolizumab) and 52 patients in phase 2 (n=40 had PD-L1-positive tumours, n=12 had PD-L1-negative tumours). The data cutoff for this analysis was Aug 7, 2017. During phase 1b, there were no dose-limiting toxicities in the dose cohorts tested. Median follow-up for the phase 2 cohort was 13·6 months (IQR 11·6–18·4) for patients with PD-L1-positive tumours, and 12·2 months (7·9–12·2) for patients with PD-L1-negative tumours. Six (15%, 90% CI 7–29) of 40 PD-L1-positive patients achieved an objective response. There were no objective responders among the PD-L1-negative patients. The most common treatment-related adverse event of any grade was fatigue (12 21% of 58 patients). Grade 3–5 adverse events occurred in 29 (50%) of patients, treatment-related grade 3–5 adverse events occurred in 17 (29%), and serious adverse events occurred in 29 (50%) patients. The most commonly occurring serious adverse events were dyspnoea (n=3 5%), pneumonitis (n=3 5%), pericardial effusion (n=2 3%), and upper respiratory infection (n=2 3%). There was one treatment-related death due to Lambert-Eaton syndrome in a PD-L1-negative patient during phase 2.
Pembrolizumab plus trastuzumab was safe and showed activity and durable clinical benefit in patients with PD-L1-positive, trastuzumab-resistant, advanced, HER2-positive breast cancer. Further studies in this breast cancer subtype should focus on a PD-L1-positive population and be done in less heavily pretreated patients.
Merck, International Breast Cancer Study Group.
The precise mechanisms underlying the beneficial effects of regulatory T (Treg) cells on long-term tissue repair remain elusive. Here, using single-cell RNA sequencing and flow cytometry, we found ...that Treg cells infiltrated the brain 1 to 5 weeks after experimental stroke in mice. Selective depletion of Treg cells diminished oligodendrogenesis, white matter repair, and functional recovery after stroke. Transcriptomic analyses revealed potent immunomodulatory effects of brain-infiltrating Treg cells on other immune cells, including monocyte-lineage cells. Microglia depletion, but not T cell lymphopenia, mitigated the beneficial effects of transferred Treg cells on white matter regeneration. Mechanistically, Treg cell-derived osteopontin acted through integrin receptors on microglia to enhance microglial reparative activity, consequently promoting oligodendrogenesis and white matter repair. Increasing Treg cell numbers by delivering IL-2:IL-2 antibody complexes after stroke improved white matter integrity and rescued neurological functions over the long term. These findings reveal Treg cells as a neurorestorative target for stroke recovery.
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•Brain-infiltrating Treg cells are essential for behavioral recovery and brain repair•Interactions between Treg cells and microglia enhance oligodendrogenesis after stroke•Treg cells secrete osteopontin to promote tissue-reparative microglial reactions•Boosting Treg numbers improves long-term outcomes after stroke
The mechanisms underlying the beneficial effects of Treg cells on stroke recovery remain unclear. Shi et al. report that brain-infiltrating Treg cells enhance brain repair after stroke. Treg-cell-derived osteopontin promotes a tissue-reparative microglial response, thereby facilitating oligodendrocyte regeneration and remyelination at the chronic stages of stroke. Boosting Treg cell numbers with an IL-2:IL-2 antibody complex improves long-term stroke recovery.
Type 1, 2, and 3 innate lymphoid cells (ILCs) have emerged as tissue-resident innate correlates of T helper 1 (Th1), Th2, and Th17 cells. Recent studies suggest that ILCs are more diverse than ...originally proposed; this might reflect truly distinct lineages or adaptation of ILCs to disparate tissue microenvironments, known as plasticity. Given that ILCs strikingly resemble T cells, are they redundant? While the regulation, timing, and magnitude of ILC and primary T cell responses differ, tissue-resident memory T cells may render ILCs redundant during secondary responses. The unique impact of ILCs in immunity is probably embodied in the extensive array of surface and intracellular receptors that endow these cells with the ability to distinguish between normal and pathogenic components, interact with other cells, and calibrate their cytokine secretion accordingly. Here I review recent advances in elucidating the diversity of ILCs and discuss their unique and redundant functions.
Innate lymphoid cells (ILCs) are tissue-resident correlates of T helper 1 (Th1), Th2, and Th17 cells. Colonna reviews recent advances in understanding ILC diversity and functional plasticity—their unique and redundant functions, receptor repertoires, and regulation of gene-expression programs.
New therapies that promote antitumour immunity have been recently developed. Most of these immunomodulatory approaches have focused on enhancing T-cell responses, either by targeting inhibitory ...pathways with immune checkpoint inhibitors, or by targeting activating pathways, as with chimeric antigen receptor T cells or bispecific antibodies. Although these therapies have led to unprecedented successes, only a minority of patients with cancer benefit from these treatments, highlighting the need to identify new cells and molecules that could be exploited in the next generation of immunotherapy. Given the crucial role of innate immune responses in immunity, harnessing these responses opens up new possibilities for long-lasting, multilayered tumour control.
The presence of multifocal tumors, developed either from intrahepatic metastasis (IM) or multicentric occurrence (MO), is a distinct feature of hepatocellular carcinoma (HCC). Immunogenomic ...characterization of multifocal HCC is important for understanding immune escape in different lesions and developing immunotherapy.
We combined whole-exome/transcriptome sequencing, multiplex immunostaining, immunopeptidomes, T cell receptor (TCR) sequencing and bioinformatic analyses of 47 tumors from 15 patients with HCC and multifocal lesions.
IM and MO demonstrated distinct clonal architecture, mutational spectrum and genetic susceptibility. The immune microenvironment also displayed spatiotemporal heterogeneity, such as less T cell and more M2 macrophage infiltration in IM and higher expression of inhibitory immune checkpoints in MO. Similar to mutational profiles, shared neoantigens and TCR repertoires among tumors from the same patients were abundant in IM but scarce in MO. Combining neoantigen prediction and immunopeptidomes identified T cell-specific neoepitopes and achieved a high verification rate in vitro. Immunoediting mainly occurred in MO but not IM, due to the relatively low immune infiltration. Loss of heterozygosity of human leukocyte antigen (HLA) alleles, identified in 17% of multifocal HCC, hampered the ability of major histocompatibility complex to present neoantigens, especially in IM. An integrated analysis of Immunoscore, immunoediting, TCR clonality and HLA loss of heterozygosity in each tumor could stratify patients into 2 groups based on whether they have a high or low risk of recurrence (p = 0.038).
Our study comprehensively characterized the genetic structure, neoepitope landscape, T cell profile and immunoediting status that collectively shape tumor evolution and could be used to optimize personalized immunotherapies for multifocal HCC.
Immunogenomic features of multifocal hepatocellular carcinoma (HCC) are important for understanding immune-escape mechanisms and developing more effective immunotherapy. Herein, comprehensive immunogenomic characterization showed that diverse genomic structures within multifocal HCC would leave footprints on the immune landscape. Only a few tumors were under the control of immunosurveillance, while others evaded the immune system through multiple mechanisms that led to poor prognosis. Our study revealed heterogeneous immunogenomic landscapes and immune-constrained tumor evolution, the understanding of which could be used to optimize personalized immunotherapies for multifocal HCC.
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•Immunogenomic discrepancies among multifocal HCC vary within patients and shape tumor evolutionary trajectories.•Immune escape involves HLA alterations, M2 macrophage infiltration, inhibitory ligands and immunoediting.•Immune context imprinted by genetics can exert selective pressures.•Immune evasion correlates with tumor regression and can predict postoperative recurrence.•Personalized immunotherapy strategies should be adopted for multifocal HCC to maximize efficacy.
Tumor neoantigen is the truly foreign protein and entirely absent from normal human organs/tissues. It could be specifically recognized by neoantigen-specific T cell receptors (TCRs) in the context ...of major histocompatibility complexes (MHCs) molecules. Emerging evidence has suggested that neoantigens play a critical role in tumor-specific T cell-mediated antitumor immune response and successful cancer immunotherapies. From a theoretical perspective, neoantigen is an ideal immunotherapy target because they are distinguished from germline and could be recognized as non-self by the host immune system. Neoantigen-based therapeutic personalized vaccines and adoptive T cell transfer have shown promising preliminary results. Furthermore, recent studies suggested the significant role of neoantigen in immune escape, immunoediting, and sensitivity to immune checkpoint inhibitors. In this review, we systematically summarize the recent advances of understanding and identification of tumor-specific neoantigens and its role on current cancer immunotherapies. We also discuss the ongoing development of strategies based on neoantigens and its future clinical applications.
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