Adjuvant dendritic cell therapy in stage IIIB/C melanoma: the MIND-DC randomized phase III trial.

Autologous natural dendritic cells (nDCs) treatment can induce tumor-specific immune responses and clinical responses in cancer patients. In this phase III clinical trial (NCT02993315), 148 patients with resected stage IIIB/C melanoma were randomized to adjuvant treatment with nDCs (n = 99) or placebo (n = 49). Active treatment consisted of intranodally injected autologous CD1c+ conventional and plasmacytoid DCs loaded with tumor antigens.

Machine learning analysis of the T cell receptor repertoire identifies sequence features of self-reactivity.

The T cell receptor (TCR) determines specificity and affinity for both foreign and self-peptides presented by the major histocompatibility complex (MHC). Although the strength of TCR interactions with self-pMHC impacts T cell function, it has been challenging to identify TCR sequence features that predict T cell fate. To discern patterns distinguishing TCRs from naive CD4 T cells with low versus high self-reactivity, we used data from 42 mice to train a machine learning (ML) algorithm that identifies population-level differences between TCRβ sequence sets.

Fumarate induces vesicular release of mtDNA to drive innate immunity.

Mutations in fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell carcinoma. Loss of FH in the kidney elicits several oncogenic signalling cascades through the accumulation of the oncometabolite fumarate. However, although the long-term consequences of FH loss have been described, the acute response has not so far been investigated.

Interpreting T-cell search "strategies" in the light of evolution under constraints.

Two decades of in vivo imaging have revealed how diverse T-cell motion patterns can be. Such recordings have sparked the notion of search "strategies": T cells may have evolved ways to search for antigen efficiently depending on the task at hand. Mathematical models have indeed confirmed that several observed T-cell migration patterns resemble a theoretical optimum; for example, frequent turning, stop-and-go motion, or alternating short and long motile runs have all been interpreted as deliberately tuned behaviours, optimising the cell's chance of finding antigen.

Listeria motility increases the efficiency of epithelial invasion during intestinal infection.

Listeria monocytogenes (Lm) is a food-borne pathogen that causes severe bacterial gastroenteritis, with high rates of hospitalization and mortality. Lm is ubiquitous in soil, water and livestock, and can survive and proliferate at low temperatures. Following oral ingestion of contaminated food, Lm crosses the epithelium through intestinal goblet cells in a mechanism mediated by Lm InlA binding host E-cadherin.

Tumor microenvironment shows an immunological abscopal effect in patients with NSCLC treated with pembrolizumab-radiotherapy combination.

Background: Immunotherapy is currently part of the standard of care for patients with advanced-stage non-small cell lung cancer (NSCLC). However, many patients do not respond to this treatment, therefore combination strategies are being explored to increase clinical benefit. The PEMBRO-RT trial combined the therapeutic programmed cell death 1 (PD-1) antibody pembrolizumab with stereotactic body radiation therapy (SBRT) to increase the overall response rate and study the effects on the tumor microenvironment (TME).

Computational modelling of cell motility modes emerging from cell-matrix adhesion dynamics.

Lymphocytes have been described to perform different motility patterns such as Brownian random walks, persistent random walks, and Lévy walks. Depending on the conditions, such as confinement or the distribution of target cells, either Brownian or Lévy walks lead to more efficient interaction with the targets. The diversity of these motility patterns may be explained by an adaptive response to the surrounding extracellular matrix (ECM).

CelltrackR: An R package for fast and flexible analysis of immune cell migration data.

Visualization of cell migration via time-lapse microscopy has greatly advanced our understanding of the immune system. However, subtle differences in migration dynamics are easily obscured by biases and imaging artifacts. While several analysis methods have been suggested to address these issues, an integrated tool implementing them is currently lacking.

Local actin dynamics couple speed and persistence in a cellular Potts model of cell migration.

Cell migration is astoundingly diverse. Molecular signatures, cell-cell interactions, and environmental structures each play their part in shaping cell motion, yielding numerous morphologies and migration modes. Nevertheless, in recent years, a simple unifying law was found to describe cell migration across many different cell types and contexts: faster cells turn less frequently.

Testing Graphical Causal Models Using the R Package "dagitty".

Causal diagrams such as directed acyclic graphs (DAGs) are used in several scientific fields to help design and analyze studies that aim to infer causal effects from observational data; for example, DAGs can help identify suitable strategies to reduce confounding bias. However, DAGs can be difficult to design, and the validity of any DAG-derived strategy hinges on the validity of the postulated DAG itself. Researchers should therefore check whether the assumptions encoded in the DAG are consistent with the data before proceeding with the analysis.

Site-specific functionality and tryptophan mimicry of lipidation in tetraspanin CD9.

Lipidation of transmembrane proteins regulates many cellular activities, including signal transduction, cell-cell communication, and membrane trafficking. However, how lipidation at different sites in a membrane protein affects structure and function remains elusive. Here, using native mass spectrometry we determined that wild-type human tetraspanins CD9 and CD81 exhibit nonstochastic distributions of bound acyl chains.

Is T Cell Negative Selection a Learning Algorithm?

Our immune system can destroy most cells in our body, an ability that needs to be tightly controlled. To prevent autoimmunity, the thymic medulla exposes developing T cells to normal "self" peptides and prevents any responders from entering the bloodstream. However, a substantial number of self-reactive T cells nevertheless reaches the periphery, implying that T cells do not encounter all self peptides during this negative selection process.

Eight-Color Multiplex Immunohistochemistry for Simultaneous Detection of Multiple Immune Checkpoint Molecules within the Tumor Microenvironment.

Therapies targeting immune checkpoint molecules CTLA-4 and PD-1/PD-L1 have advanced the field of cancer immunotherapy. New mAbs targeting different immune checkpoint molecules, such as TIM3, CD27, and OX40, are being developed and tested in clinical trials. To make educated decisions and design new combination treatment strategies, it is vital to learn more about coexpression of both inhibitory and stimulatory immune checkpoints on individual cells within the tumor microenvironment.

Surviving Stress: Modulation of ATF4-Mediated Stress Responses in Normal and Malignant Cells.

Activating transcription factor 4 (ATF4) is a stress-induced transcription factor that is frequently upregulated in cancer cells. ATF4 controls the expression of a wide range of adaptive genes that allow cells to endure periods of stress, such as hypoxia or amino acid limitation. However, under persistent stress conditions, ATF4 promotes the induction of apoptosis.

Human CD1c(+) DCs are critical cellular mediators of immune responses induced by immunogenic cell death.

Chemotherapeutics, including the platinum compounds oxaliplatin (OXP) and cisplatin (CDDP), are standard care of treatment for cancer. Although chemotherapy has long been considered immunosuppressive, evidence now suggests that certain cytotoxic agents can efficiently stimulate antitumor responses, through the induction of a form of apoptosis, called immunogenic cell death (ICD). ICD is characterized by exposure of calreticulin and heat shock proteins (HSPs), secretion of ATP and release of high-mobility group box 1 (HMGB1).