PD-1 Blockade and CD27 Stimulation Activate Distinct Transcriptional Programs That Synergize for CD8 T-Cell-Driven Antitumor Immunity.

PD-1 checkpoint blockade has revolutionized the field of cancer immunotherapy, yet the frequency of responding patients is limited by inadequate T-cell priming secondary to a paucity of activatory dendritic cells (DC). DC signals can be bypassed by CD27 agonists, and we therefore investigated if the effectiveness of anti-PD-1/L1 could be improved by combining with agonist anti-CD27 monoclonal antibodies (mAb). The efficacy of PD-1/L1 blockade or agonist anti-CD27 mAb was compared with a dual-therapy approach in multiple tumor models.

CD27 costimulation contributes substantially to the expansion of functional memory CD8(+) T cells after peptide immunization.

Naive T cells require signals from multiple costimulatory receptors to acquire full effector function and differentiate to long-lived memory cells. The costimulatory receptor, CD27, is essential for optimal T-cell priming and memory differentiation in a variety of settings, although whether CD27 is similarly required during memory CD8(+) T-cell reactivation remains controversial. We have used OVA and anti-CD40 to establish a memory CD8(+) T-cell population and report here that their secondary expansion, driven by peptide and anti-CD40, polyI:C, or LPS, requires CD27.

CD70-CD27 interaction augments CD8+ T-cell activation by human epidermal Langerhans cells.

Human cutaneous dendritic cells (DCs) from epidermal and dermal compartments exhibit functional differences in their induction of CD4+ T-cell and humoral immune responses; however, differences in the regulation of memory CD8+ T-cell responses by human skin DCs remain poorly characterized. We tested the capacity of human Langerhans cells (LCs) and dermal dendritic cells (DDCs) to induce antigen-specific cytokine production and proliferation of memory CD8+ cells. Although tumor necrosis factor-α-matured human DCs from both epidermal and dermal compartments showed efficient potential to activate CD8+ cells, LCs were constitutively more efficient than DDCs in cross-presenting CD8+ epitopes, as well as direct presentation of viral antigen to Epstein-Barr virus-specific CD8+ T cells.

Death receptor 3 is essential for generating optimal protective CD4⁺ T-cell immunity against Salmonella.

The TNF receptor superfamily member death receptor 3 (DR3) exacerbates Th2- and Th17-cell-mediated inflammatory and autoimmune conditions, yet no role in host defence has been reported. Here, we examined the role of DR3 during infection with Salmonella enterica serovar Typhimurium. Infection resulted in protracted expression of the DR3 ligand TL1A but not the related TNF superfamily proteins OX40L or CD30L.

Triggering of TNFRSF25 promotes CD8⁺ T-cell responses and anti-tumor immunity.

TNFRSF25 is a member of the TNF receptor superfamily (TNFRSF) that binds to the TNF-like protein TL1A. Although recent studies have demonstrated a role for TNFRSF25 in regulating CD4(+) T-cell responses, it remains to be determined if TNFRSF25 functions as a costimulatory receptor for CD8(+) T cells. Here, we demonstrate that ectopic expression of TL1A on mouse plasmacytomas promotes elimination of tumor cells in a CD8(+) T-cell-dependent manner and renders mice immune to a subsequent challenge with tumor cells.

Sustained TL1A expression modulates effector and regulatory T-cell responses and drives intestinal goblet cell hyperplasia.

The tumor necrosis factor (TNF) superfamily protein TNF-like 1A (TL1A) is the ligand for death receptor 3 (DR3). TL1A is induced on activated dendritic cells (DCs) and its expression has been linked to human inflammatory bowel disease. To address how TL1A might influence intestinal inflammation, we generated transgenic mice that constitutively express TL1A on DCs.

The Death Receptor 3-TNF-like protein 1A pathway drives adverse bone pathology in inflammatory arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease of synovial joints that is associated with cartilage and bone destruction. Death Receptor 3 (DR3), a tumor necrosis factor (TNF) receptor superfamily member, has recently been associated with the pathogenesis of RA. We demonstrate that absence of DR3 confers resistance to the development of adverse bone pathology in experimental antigen-induced arthritis (AIA).

Invariant NKT cells promote CD8+ cytotoxic T cell responses by inducing CD70 expression on dendritic cells.

Activation of invariant NK T (iNKT) cells with the glycolipid alpha-galactosylceramide promotes CD8(+) cytotoxic T cell responses, a property that has been used to enhance the efficacy of antitumor vaccines. Using chimeric mice, we now show that the adjuvant properties of iNKT cells require that CD40 triggering and Ag presentation to CD8(+) T cells occur on the same APCs. We demonstrate that injection of alpha-galactosylceramide triggers CD70 expression on splenic T cell zone dendritic cells and that this is dependent on CD40 signaling.

Cell therapy of comatose states.

We demonstrated that liquor from adult humans can maintain proliferative activity of cells of immature nervous tissue in vitro. The paper presents the results of a retrospective clinical study of the efficiency of cell therapy in the treatment of II-III degree comatose patients with severe brain injury. Cell suspension consisting of cells derived from immature nervous and hemopoietic tissues was injected into the recipient subarachnoidal space through a cerebrospinal puncture.

Eradication of lymphoma by CD8 T cells following anti-CD40 monoclonal antibody therapy is critically dependent on CD27 costimulation.

Growing evidence points to the potential of agonistic anti-CD40 mAbs as adjuvants for vaccination against cancer. These appear to act by maturing dendritic cells (DCs) and allowing them to prime CD8 cytotoxic T lymphocytes (CTLs). Although it is well established that optimal T-cell priming requires costimulation via B7:CD28, recent studies emphasize the contribution of TNF receptors to this process.

Requirement for CD70 in CD4+ Th cell-dependent and innate receptor-mediated CD8+ T cell priming.

Dendritic cell (DC) conditioning by CD4+ T cells, or via engagement of innate receptors, is thought to be essential for CD8+ T cell priming. However, the molecular features that distinguish a conditioned DC from an unconditioned DC are poorly defined. In this study, we investigate the role of CD70, a member of the TNF superfamily that is expressed on activated DC, in CD4+ Th-dependent and -independent CD8+ T cell responses.

Cell therapy of brain stroke.

Cell suspension consisting of cells from immature nervous and hemopoietic tissues was subarachnoidally transplanted to 10 patients with brain stroke consequences. Clinical effect of different degree was attained in all patients. Six months after cell therapy functional activity significantly increased in contrast to clinically comparable control group.

Antimicrobial resistance of nosocomial strains of Staphylococcus aureus in Russia: results of a prospective study.

A total of 879 Staphylococcus aureus clinical isolates from 17 medical institutions in different regions of Russia were tested. Susceptibility to 18 antimicrobials was determined by agar dilution in accordance with the NCCLS recommendations. The most potent antimicrobials were glycopeptides, linezolid, and fusidic acid, to which no resistance was found.

Cutting edge: a critical role for CD70 in CD8 T cell priming by CD40-licensed APCs.

The CD154/CD40 interaction is an important pathway of CD4 T cell help for CD8 T cell responses. In this study, we address the role of CD70, a member of the TNF superfamily and the ligand for the T cell costimulatory receptor CD27, in CD40-mediated priming of CD8 T cells. Using an agonistic anti-CD40 mAb to mimic the CD154/CD40 interaction we demonstrate that the priming of OT-I TCR transgenic or endogenous mouse OVA-specific CD8 T cells is critically dependent on CD70/CD27 interaction.

Transplantation treatment of spinal cord injury patients.

The minimally manipulated cells from fetal nervous and hemopoietic tissues (gestational age 16-22 weeks) were subarachnoidally implanted into 15 patients (18-52 years old) with severe consequences of traumatic spinal cord injury (SCI) at cervical or thoracic spine level. The times after SCI were from 1 month to 6 years. Each patient underwent from one to four cell transplantations (CT) with various time intervals.

Bone Marrow Cells in Suppressing Leukemic Cell Growth.

In this paper we review our experimental findings concerning the capacity of bone marrow cells (BMC) to control leukemic cell growth. It has been shown that the cells isolated from normal bone marrow can provide dose dependent suppression of the proliferative activity of leukemic cells in vitro. BMC cytostatic effect is antigen non-specific and does not associate with cell death.

Expression and costimulatory effects of the TNF receptor superfamily members CD134 (OX40) and CD137 (4-1BB), and their role in the generation of anti-tumor immune responses.

This study addresses the relative importance of CD134 (OX40) and CD137 (4-1BB) in the costimulation of CD4+ and CD8+ T cells under comparable conditions of antigenic stimulation. We demonstrate that CD134 is capable of directly costimulating CD8+ T cells. However, costimulation of CD8+ T cells by CD134 is less potent than that triggered by CD137.

Soluble factor and cell-cell interaction in cytostasis induced by bone marrow cells.

Cell-cell interaction and soluble low-molecular-weight products are probably involved in in vitro inhibition of leukemic cell growth by bone marrow cells.

Characterization of erythroid cell-derived natural suppressor activity.

Nucleated erythroid cells (NEC) have been previously reported to the capable of suppressing antibody-mediated primary (IgM) and secondary (IgG) immune responses to thymus-dependent antigens. In the present study we indicated that NEC, separated from the spleens of mice following phenylhydrazine treatment were able to suppress directly the proliferative response of preactivated B cells to lipopolysaccharide (LPS) in vitro. While being active in suppressing B cell blastogenesis, NEC, however, failed to reduce both cell proliferation and cytotoxic T lymphocyte (CTL) generation in an allogeneic mixed lymphocyte culture (MLC).