Prognostic value of tertiary lymphoid structures in triple-negative breast cancer: integrated analysis with the tumor microenvironment and clinicopathological features.

Background: In triple-negative breast cancer (TNBC), the most immunogenic breast cancer type, tumor-infiltrating lymphocytes (TILs) are an independent prognostic factor. Tertiary lymphoid structures (TLS) are an important TILs source, but they are not integrated in the current prognostic criteria.

Methods: In this retrospective study, TLS were assessed in hematein-eosin-saffron-stained (HES) histological sections from 397 early, chemotherapy-naive TNBC samples after primary surgical resection.

Monitoring mAb proteoforms in mouse plasma using an automated immunocapture combined with top-down and middle-down mass spectrometry.

Monoclonal antibodies (mAbs) have established themselves as the leading biopharmaceutical therapeutic modality. Once the developability of a mAb drug candidate has been assessed, an important step is to check its in vivo stability through pharmacokinetics (PK) studies. The gold standard is ligand-binding assay (LBA) and liquid chromatography-mass spectrometry (LC-MS) performed at the peptide level (bottom-up approach).

Single-cell high-dimensional imaging mass cytometry: one step beyond in oncology.

Solid tumors have a dynamic ecosystem in which malignant and non-malignant (endothelial, stromal, and immune) cell types constantly interact. Importantly, the abundance, localization, and functional orientation of each cell component within the tumor microenvironment vary significantly over time and in response to treatment. Such intratumoral heterogeneity influences the tumor course and its sensitivity to treatments.

A Selection of Macrocyclic Peptides That Bind STING From an mRNA-Display Library With Split Degenerate Codons.

Recent improvements in mRNA display have enabled the selection of peptides that incorporate non-natural amino acids, thus expanding the chemical diversity of macrocycles beyond what is accessible in nature. Such libraries have incorporated non-natural amino acids at the expense of natural amino acids by reassigning their codons. Here we report an alternative approach to expanded amino-acid diversity that preserves all 19 natural amino acids (no methionine) and adds 6 non-natural amino acids, resulting in the highest sequence complexity reported to date.

Clinicopathological Correlates of γδ T Cell Infiltration in Triple-Negative Breast Cancer.

The prognostic impact of the different tumor-infiltrating lymphocyte (TIL) subpopulations in solid cancers is still debated. Here, we investigated the clinicopathological correlates and prognostic impact of TILs, particularly of γδ T cells, in 162 patients with triple-negative breast cancer (TNBC). A high γδ T cell density (>6.

Pro-tumor γδ T Cells in Human Cancer: Polarization, Mechanisms of Action, and Implications for Therapy.

The tumor immune microenvironment contributes to tumor initiation, progression and response to therapy. Among the immune cell subsets that play a role in the tumor microenvironment, innate-like T cells that express T cell receptors composed of γ and δ chains (γδ T cells) are of particular interest. Indeed, γδ T cells contribute to the immune response against many cancers, notably through their powerful effector functions that lead to the elimination of tumor cells and the recruitment of other immune cells.

Diversity of Tumor-Infiltrating, γδ T-Cell Abundance in Solid Cancers.

γδ T-cells contribute to the immune response against many tumor types through their direct cytolytic functions and their capacity to recruit and regulate the biological functions of other immune cells. As potent effectors of the anti-tumor immune response, they are considered an attractive therapeutic target for immunotherapies, but their presence and abundance in the tumor microenvironment are not routinely assessed in patients with cancer. Here, we validated an antibody for immunohistochemistry analysis that specifically detects all γδ T-cell subpopulations in healthy tissues and in the microenvironment of different cancer types.

Identification of a regulatory Vδ1 gamma delta T cell subpopulation expressing CD73 in human breast cancer.

γδ T cells contribute to the immune response against many cancers, notably through their powerful effector functions that lead to the elimination of tumor cells and the recruitment of other immune cells. However, their presence in the tumor microenvironment has been associated with poor prognosis in breast, colon, and pancreatic cancer, suggesting that γδ T cells may also display pro-tumor activities. Here, we identified in blood from healthy donors a subpopulation of Vδ1T cells that represents around 20% of the whole Vδ1 population, expresses CD73, and displays immunosuppressive phenotype and functions (i.

IL-21 Signaling in the Tumor Microenvironment.

IL-21 is an immunomodulatory cytokine produced by natural killer (NK) cells and T cells that has pleiotropic roles in immune and nonimmune cells. IL-21 can modulate innate and specific immunity activities. It is a potent stimulator of T and natural killer cell-mediated antitumor immunity but also has pro-inflammatory functions in many tissues and is involved in oncogenesis.

Adnectin-drug conjugates for Glypican-3-specific delivery of a cytotoxic payload to tumors.

Tumor-specific delivery of cytotoxic agents remains a challenge in cancer therapy. Antibody-drug conjugates (ADC) deliver their payloads to tumor cells that overexpress specific tumor-associated antigens-but the multi-day half-life of ADC leads to high exposure even of normal, antigen-free, tissues and thus contributes to dose-limiting toxicity. Here, we present Adnectin-drug conjugates, an alternative platform for tumor-specific delivery of cytotoxic payloads.

PD-1 blockade at the time of tumor escape potentiates the immune-mediated antitumor effects of a melanoma-targeting monoclonal antibody.

Tumor antigen-targeting monoclonal antibodies (TA-targeting mAbs) are used as therapeutics in many malignancies and their capacity to mobilize the host immunity puts them at the forefront of anti-cancer immunotherapies. Both innate and adaptive immune cells have been associated with the therapeutic activity of such antibodies, but tumor escape from mAb-induced tumor immune surveillance remains one of the main clinical issues. In this preclinical study, we grafted immunocompetent and immunocompromised mice with the B16F10 mouse melanoma cell line and treated them with the TA99 TA-targeting mAb to analyze the immune mechanisms associated with the tumor response and resistance to TA99 monotherapy.

Synthesis and Biologic Evaluation of a Novel F-Labeled Adnectin as a PET Radioligand for Imaging PD-L1 Expression.

The programmed death protein (PD-1) and its ligand (PD-L1) play critical roles in a checkpoint pathway cancer cells exploit to evade the immune system. A same-day PET imaging agent for measuring PD-L1 status in primary and metastatic lesions could be important for optimizing drug therapy. Herein, we have evaluated the tumor targeting of an anti-PD-L1 adnectin after F-fluorine labeling.

Radiosynthesis and preclinical PET evaluation of Zr-nivolumab (BMS-936558) in healthy non-human primates.

Cancer immunotherapy, unlike traditional cytotoxic chemotherapeutic treatments, engages the immune system to identify cancer cells and stimulate immune responses. The Programmed Death-1 (PD-1) protein is an immunoinhibitory receptor expressed by activated cytotoxic T-lymphocytes (CTL) that seek out and destroy cancer cells. Multiple cancer types express and upregulate the Programmed Death-Ligand 1 (PD-L1) and 2 (PD-L2) which bind to PD-1 as an immune escape mechanism.

Relearning of Activities of Daily Living: A Comparison of the Effectiveness of Three Learning Methods in Patients with Dementia of the Alzheimer Type.

This study examined the effectiveness of three different learning methods: trial and error learning (TE), errorless learning (EL) and learning by modeling with spaced retrieval (MR) on the relearning process of IADL in mild-to-moderately severe Alzheimer's Dementia (AD) patients (n=52), using a 6-weeks randomized controlled trial design. The participants had to relearn three IADLs. Repeated-measure analyses during pre-intervention, post-intervention and 1-month delayed sessions were performed.

[Alzheimer's disease and the organization of visits to cultural sites].

In the framework of a policy to open up cultural sites within the city to the specific disability of Alzheimer's disease, the Resource and Research Memory Centre at Nice general hospital in partnership with Nice's city hall, has developed a cultural programme. The aim of this project is to assess the therapeutic aspects of this programme and notably the perception of the disease by the family carers.

Tumor antigen-targeting monoclonal antibody-based immunotherapy: Orchestrating combined strategies for the development of long-term antitumor immunity.

Tumor antigen (TA)-targeting monoclonal antibody (mAb)-based treatments are considered to be one of the most successful strategies in cancer therapy. Besides targeting TAs and inducing tumor cell death, such antibodies interact with immune cells through Fc-dependent mechanisms to induce adaptive memory immune responses. However, multiple inhibitory/immunosuppressive pathways can be induced by tumor cells to limit the establishment of an efficient antitumor response and consequently a sustained clinical response to TA-targeting mAbs.

Development and Fit-for-Purpose Validation of a Soluble Human Programmed Death-1 Protein Assay.

Programmed death-1 (PD-1) protein is a co-inhibitory receptor which negatively regulates immune cell activation and permits tumors to evade normal immune defense. Anti-PD-1 antibodies have been shown to restore immune cell activation and effector function-an exciting breakthrough in cancer immunotherapy. Recent reports have documented a soluble form of PD-1 (sPD-1) in the circulation of normal and disease state individuals.

Plasticity of γδ T Cells: Impact on the Anti-Tumor Response.

The tumor immune microenvironment contributes to tumor initiation, progression, and response to therapy. Among the immune cell subsets that play a role in the tumor microenvironment, innate-like T cells that express T cell receptors composed of γ and δ chains (γδ T cells) are of particular interest. γδ T cells can contribute to the immune response against many tumor types (lymphoma, myeloma, melanoma, breast, colon, lung, ovary, and prostate cancer) directly through their cytotoxic activity and indirectly by stimulating or regulating the biological functions of other cell types required for the initiation and establishment of the anti-tumor immune response, such as dendritic cells and cytotoxic CD8+ T cells.

Full restoration of Brucella-infected dendritic cell functionality through Vγ9Vδ2 T helper type 1 crosstalk.

Vγ9Vδ2 T cells play an important role in the immune response to infectious agents but the mechanisms contributing to this immune process remain to be better characterized. Following their activation, Vγ9Vδ2 T cells develop cytotoxic activity against infected cells, secrete large amounts of cytokines and influence the function of other effectors of immunity, notably cells playing a key role in the initiation of the adaptive immune response such as dendritic cells. Brucella infection dramatically impairs dendritic cell maturation and their capacity to present antigens to T cells.

Role of NKG2D and its ligands in the anti-infectious activity of Vγ9Vδ2 T cells against intracellular bacteria.

Human Vγ9Vδ2 T cells play a crucial role in early immune response to intracellular pathogens. Their number is drastically increased in the peripheral blood of patients during the acute phase of brucellosis. In vitro, Vγ9Vδ2 T cells exhibit strong cytolytic activity against Brucella-infected cells and impair intracellular growth of Brucella suis in autologous macrophages.

The new species Brucella microti replicates in macrophages and causes death in murine models of infection.

Background: The recent isolation of Brucella microti from the common vole, the red fox, and the soil raises the possibility of an eventual reemergence of brucellosis in Europe. In this work, the pathogenic potential of this new Brucella species in both in vitro and in vivo models of infection was analyzed.

Methods: The ability of B.

How much binding affinity can be gained by filling a cavity?

Binding affinity optimization is critical during drug development. Here, we evaluate the thermodynamic consequences of filling a binding cavity with functionalities of increasing van der Waals radii (-H, -F, -Cl, and CH(3)) that improve the geometric fit without participating in hydrogen bonding or other specific interactions. We observe a binding affinity increase of two orders of magnitude.