Immune checkpoint therapy responders display early clonal expansion of tumor infiltrating lymphocytes.

Immune checkpoint therapy (ICT) causes durable tumour responses in a subgroup of patients, but it is not well known how T cell receptor beta (TCRß) repertoire dynamics contribute to the therapeutic response. Using murine models that exclude variation in host genetics, environmental factors and tumour mutation burden, limiting variation between animals to naturally diverse TCRß repertoires, we applied TCRseq, single cell RNAseq and flow cytometry to study TCRß repertoire dynamics in ICT responders and non-responders. Increased oligoclonal expansion of TCRß clonotypes was observed in responding tumours. Machine learning identified TCRß CDR3 signatures unique to each tumour model, and signatures associated with ICT response at various timepoints before or during ICT. Clonally expanded CD8+ T cells in responding tumours post ICT displayed effector T cell gene signatures and phenotype. An early burst of clonal expansion during ICT is associated with response, and we report unique dynamics in TCRß signatures associated with ICT response.

Reservoir time series analysis: Using the response of complex dynamical systems as a universal indicator of change.

We present the idea of reservoir time series analysis (RTSA), a method by which the state space representation generated by a reservoir computing (RC) model can be used for time series analysis. We discuss the motivation for this with reference to the characteristics of RC and present three ad hoc methods for generating representative features from the reservoir state space. We then develop and implement a hypothesis test to assess the capacity of these features to distinguish signals from systems with varying parameters. In comparison to a number of benchmark approaches (statistical, Fourier, phase space, and recurrence analysis), we are able to show significant, generalized accuracy across the proposed RTSA features that surpasses the benchmark methods. Finally, we briefly present an application for bearing fault distinction to motivate the use of RTSA in application.

Multiple Sensors Data Integration for Traffic Incident Detection Using the Quadrant Scan.

Non-recurrent congestion disrupts normal traffic operations and lowers travel time (TT) reliability, which leads to many negative consequences such as difficulties in trip planning, missed appointments, loss in productivity, and driver frustration. Traffic incidents are one of the six causes of non-recurrent congestion. Early and accurate detection helps reduce incident duration, but it remains a challenge due to the limitation of current sensor technologies. In this paper, we employ a recurrence-based technique, the Quadrant Scan, to analyse time series traffic volume data for incident detection. The data is recorded by multiple sensors along a section of urban highway. The results show that the proposed method can detect incidents better by integrating data from the multiple sensors in each direction, compared to using them individually. It can also distinguish non-recurrent traffic congestion caused by incidents from recurrent congestion. The results show that the Quadrant Scan is a promising algorithm for real-time traffic incident detection with a short delay. It could also be extended to other non-recurrent congestion types.

Quadrant scan for multi-scale transition detection.

Transition detection in temporal and nontemporal signals is a problem encountered in various disciplines. We investigate the quadrant scan technique to analyze recurrence plots to identify tipping points of a dynamical system. We define two types of transition, state-transition and dynamic-transition, and prove analytically the ability of quadrant scans to detect both types. We then provide an extension by considering a weighting scheme to overcome limitations of the standard scheme. We further highlight the merits of the quadrant scan and our extension by studying several applications. The ability of the quadrant scan and its extension to deal with nontemporal, multivariate, or large data sets as well as their capability to classify multiscale transitions are demonstrated in detail through several examples and settings.

Sensitization to immune checkpoint blockade through activation of a STAT1/NK axis in the tumor microenvironment.

Cancer immunotherapy using antibodies that target immune checkpoints has delivered outstanding results. However, responses only occur in a subset of patients, and it is not fully understood what biological processes determine an effective outcome. This lack of understanding hinders the development of rational combination treatments. We set out to define the pretreatment microenvironment associated with an effective outcome by using the fact that inbred mouse strains bearing monoclonal cancer cell line-derived tumors respond in a dichotomous manner to immune checkpoint blockade (ICB). We compared the cellular composition and gene expression profiles of responsive and nonresponsive tumors from mice before ICB and validated the findings in cohorts of patients with cancer treated with ICB antibodies. We found that responsive tumors were characterized by an inflammatory gene expression signature consistent with up-regulation of signal transducer and activator of transcription 1 (STAT1) and Toll-like receptor 3 (TLR3) signaling and down-regulation of interleukin-10 (IL-10) signaling. In addition, responsive tumors had more infiltrating-activated natural killer (NK) cells, which were necessary for response. Pretreatment of mice with large established tumors using the STAT1-activating cytokine interferon-γ (IFNγ), the TLR3 ligand poly(I:C), and an anti-IL-10 antibody sensitized tumors to ICB by attracting IFNγ-producing NK cells into the tumor, resulting in increased cure rates. Our results identify a pretreatment tumor microenvironment that predicts response to ICB, which can be therapeutically attained. These data suggest a biomarker-driven approach to patient management to establish whether a patient would benefit from treatment with sensitizing therapeutics before ICB.

Optimal Shadowing Filter for a Positioning and Tracking Methodology with Limited Information.

Positioning and tracking a moving target from limited positional information is a frequently-encountered problem. For given noisy observations of the target's position, one wants to estimate the true trajectory and reconstruct the full phase space including velocity and acceleration. The shadowing filter offers a robust methodology to achieve such an estimation and reconstruction. Here, we highlight and validate important merits of this methodology for real-life applications. In particular, we explore the filter's performance when dealing with correlated or uncorrelated noise, irregular sampling in time and how it can be optimised even when the true dynamics of the system are not known.

Tracking a single pigeon using a shadowing filter algorithm.

Miniature GPS devices now allow for measurement of the movement of animals in real time and provide high- quality and high-resolution data. While these new data sets are a great improvement, one still encounters some measurement errors as well as device failures. Moreover, these devices only measure position and require further reconstruction techniques to extract the full dynamical state space with the velocity and acceleration. Direct differentiation of position is generally not adequate. We report on the successful implementation of a shadowing filter algorithm that (1) minimizes measurement errors and (2) reconstructs at the same time the full phase-space from a position recording of a flying pigeon. This filter is based on a very simple assumption that the pigeon's dynamics are Newtonian. We explore not only how to choose the filter's parameters but also demonstrate its improvements over other techniques and give minimum data requirements. In contrast to competing filters, the shadowing filter's approach has not been widely implemented for practical problems. This article addresses these practicalities and provides a prototype for such application.