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Candida spp. Determination and Th1/Th2 Mixed Cytokine Profile in Oral Samples From HIV+ Patients With Chronic Periodontitis
2019
Background: Chronic periodontitis (CP), caused by bacteria and fungi, appears in up to 66% of HIV-patients. The impact and association of HIV-treatment (HAART) and Candida itself has not been properly evaluated in the development and progression of CP. The immunopathogenesis is characterized by CD4+ T-cells activation and the balance between the T-helper 1 (Th1) and T-helper 2 (Th2) or a mixed cytokine profile. Currently, the associated causes of an immune response in HIV-patients with CP is controversial. Our aims were the determination of Candida spp. and cytokine profile in oral samples from HIV-positive patients with CP, considering the CD4+ T cells levels and HAART use.Methods: From 50…
A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets.
2018
International audience; NKp46 (CD335) is a surface receptor shared by both human and mouse natural killer (NK) cells and innate lymphoid cells (ILCs) that transduces activating signals necessary to eliminate virus-infected cells and tumors. Here, we describe a spontaneous point mutation of cysteine to arginine (C14R) in the signal peptide of the NKp46 protein in congenic Ly5.1 mice and the newly generated NCR(B6C14R) strain. Ly5.1(C14R) NK cells expressed similar levels of Ncr1 mRNA as C57BL/6, but showed impaired surface NKp46 and reduced ability to control melanoma tumors in vivo. Expression of the mutant NKp46(C14R) in 293T cells showed that NKp46 protein trafficking to the cell surface …
RUNX3 and T-Bet in Immunopathogenesis of Ankylosing Spondylitis—Novel Targets for Therapy?
2019
Susceptibility to ankylosing spondylitis (AS) is polygenic with more than 100 genes identified to date. These include HLA-B27 and the aminopeptidases (ERAP1, ERAP2, and LNPEPS), which are involved in antigen processing and presentation to T-cells, and several genes (IL23R, IL6R, STAT3, JAK2, IL1R1/2, IL12B, and IL7R) involved in IL23 driven pathways of inflammation. AS is also strongly associated with polymorphisms in two transcription factors, RUNX3 and T-bet (encoded by TBX21), which are important in T-cell development and function. The influence of these genes on the pathogenesis of AS and their potential for identifying drug targets is discussed here.
Mycobacterium tuberculosis Drives Expansion of Low-Density Neutrophils Equipped With Regulatory Activities
2019
In human tuberculosis (TB) neutrophils represent the most commonly infected phagocyte but their role in protection and pathology is highly contradictory. Moreover, a subset of low-density neutrophils (LDNs) has been identified in TB, but their functions remain unclear. Here, we have analyzed total neutrophils and their low-density and normal-density (NDNs) subsets in patients with active TB disease, in terms of frequency, phenotype, functional features, and gene expression signature. Full-blood counts from Healthy Donors (H.D.), Latent TB infected, active TB, and cured TB patients were performed. Frequency, phenotype, burst activity, and suppressor T cell activity of the two different subse…
Bovine herpesvirus 4-based vector delivering the full length xCT DNA efficiently protects mice from mammary cancer metastases by targeting cancer ste…
2018
Despite marked advancements in its treatment, breast cancer is still the second leading cause of cancer death in women, due to relapses and distal metastases. Breast cancer stem cells (CSCs), are a cellular reservoir for recurrence, metastatic evolution and disease progression, making the development of novel therapeutics that target CSCs, and thereby inhibit metastases, an urgent need. We have previously demonstrated that the cystine-glutamate antiporter xCT (SLC7A11), a protein that was shown to be overexpressed in mammary CSCs and that plays a key role in the maintenance of their redox balance, self-renewal and resistance to chemotherapy, is a potential target for mammary cancer immunoth…
Evolution of melanoma cross-resistance to CD8⁺ T cells and MAPK inhibition in the course of BRAFi treatment
2018
The profound but frequently transient clinical responses to BRAFV600 inhibitor (BRAFi) treatment in melanoma emphasize the need for combinatorial therapies. Multiple clinical trials combining BRAFi and immunotherapy are under way to further enhance therapeutic responses. However, to which extent BRAFV600 inhibition may affect melanoma immunogenicity over time remains largely unknown. To support the development of an optimal treatment protocol, we studied the impact of prolonged BRAFi exposure on the recognition of melanoma cells by T cells in different patient models. We demonstrate that autologous CD8+ tumor-infiltrating lymphocytes (TILs) efficiently recognized short-term (3, 7 days) BRAF…
Autoantigens in the trabecular meshwork and glaucoma‐specific alterations in the natural autoantibody repertoire
2019
Abstract Objectives Primary open‐angle glaucoma (POAG) is a neurodegenerative disorder leading to a gradual vision loss caused by progressive damage to the optic nerve. Immunological processes are proposed to be involved in POAG pathogenesis. Altered serological autoantibody levels have been frequently reported, but complete analyses of the natural autoantibodies with respect to disease‐related alterations are scarce. Here, we provide an explorative analysis of pathways and biological processes that may involve naturally immunogenic proteins and highlight POAG‐specific alterations. Methods Mass spectrometry‐based antibody‐mediated identification of autoantigens (MS‐AMIDA) was carried out in…
Targeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy
2018
The approval of the first two monoclonal antibodies targeting CD38 (daratumumab) and SLAMF7 (elotuzumab) in late 2015 for treating relapsed and refractory multiple myeloma (RRMM) was a critical advance for immunotherapies for multiple myeloma (MM). Importantly, the outcome of patients continues to improve with the incorporation of this new class of agents with current MM therapies. However, both antigens are also expressed on other normal tissues including hematopoietic lineages and immune effector cells, which may limit their long-term clinical use. B cell maturation antigen (BCMA), a transmembrane glycoprotein in the tumor necrosis factor receptor superfamily 17 (TNFRSF17), is expressed a…
A multicenter phase 1 study of solitomab (MT110, AMG 110), a bispecific EpCAM/CD3 T-cell engager (BiTE®) antibody construct, in patients with refract…
2018
ABSTRACT We assessed the tolerability and antitumor activity of solitomab, a bispecific T-cell engager (BiTE®) antibody construct targeting epithelial cell adhesion molecule (EpCAM). Patients with relapsed/refractory solid tumors not amenable to standard therapy received solitomab as continuous IV infusion in a phase 1 dose-escalation study with six different dosing schedules. The primary endpoint was frequency and severity of adverse events (AEs). Secondary endpoints included pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity. Sixty-five patients received solitomab at doses between 1 and 96 µg/day for ≥28 days. Fifteen patients had dose-limiting toxicities (DLTs): e…
Responsiveness to anti-PD-1 and anti-CTLA-4 immune checkpoint blockade in SB28 and GL261 mouse glioma models.
2018
Immune checkpoint blockade (ICB) is currently evaluated in patients with glioblastoma (GBM), based on encouraging clinical data in other cancers, and results from studies with the methylcholanthrene-induced GL261 mouse glioma. In this paper, we describe a novel model faithfully recapitulating some key human GBM characteristics, including low mutational load, a factor reported as a prognostic indicator of ICB response. Consistent with this observation, SB28 is completely resistant to ICB, contrasting with treatment sensitivity of the more highly mutated GL261. Moreover, SB28 shows features of a poorly immunogenic tumor, with low MHC-I expression and modest CD8(+) T-cell infiltration, suggest…