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"Pierce, Robert"
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Immune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma
Cutaneous T cell lymphomas (CTCL) are rare but aggressive cancers without effective treatments. While a subset of patients derive benefit from PD-1 blockade, there is a critically unmet need for predictive biomarkers of response. Herein, we perform CODEX multiplexed tissue imaging and RNA sequencing on 70 tumor regions from 14 advanced CTCL patients enrolled in a pembrolizumab clinical trial (NCT02243579). We find no differences in the frequencies of immune or tumor cells between responders and non-responders. Instead, we identify topographical differences between effector PD-1
+
CD4
+
T cells, tumor cells, and immunosuppressive Tregs, from which we derive a spatial biomarker, termed the
SpatialScore
, that correlates strongly with pembrolizumab response in CTCL. The
SpatialScore
coincides with differences in the functional immune state of the tumor microenvironment, T cell function, and tumor cell-specific chemokine recruitment and is validated using a simplified, clinically accessible tissue imaging platform. Collectively, these results provide a paradigm for investigating the spatial balance of effector and suppressive T cell activity and broadly leveraging this biomarker approach to inform the clinical use of immunotherapies.
PD-1 blockade is effective for only a subset of patients with cutaneous T cell lymphomas. Here, the authors report a spatial biomarker that uses immune and cancer cell topography to predict response to PD-1 blockade in this disease.
Journal Article
Tumor immune profiling predicts response to anti–PD-1 therapy in human melanoma
Immune checkpoint blockade is revolutionizing therapy for advanced cancer, but many patients do not respond to treatment. The identification of robust biomarkers that predict clinical response to specific checkpoint inhibitors is critical in order to stratify patients and to rationally select combinations in the context of an expanding array of therapeutic options.
We performed multiparameter flow cytometry on freshly isolated metastatic melanoma samples from 2 cohorts of 20 patients each prior to treatment and correlated the subsequent clinical response with the tumor immune phenotype.
Increasing fractions of programmed cell death 1 high/cytotoxic T lymphocyte-associated protein 4 high (PD-1hiCTLA-4hi) cells within the tumor-infiltrating CD8+ T cell subset strongly correlated with response to therapy (RR) and progression-free survival (PFS). Functional analysis of these cells revealed a partially exhausted T cell phenotype. Assessment of metastatic lesions during anti-PD-1 therapy demonstrated a release of T cell exhaustion, as measured by an accumulation of highly activated CD8+ T cells within tumors, with no effect on Tregs.
Our data suggest that the relative abundance of partially exhausted tumor-infiltrating CD8+ T cells predicts response to anti-PD-1 therapy. This information can be used to appropriately select patients with a high likelihood of achieving a clinical response to PD-1 pathway inhibition.
This work was funded by a generous gift provided by Inga-Lill and David Amoroso as well as a generous gift provided by Stephen Juelsgaard and Lori Cook.
Journal Article
PD-1 blockade induces responses by inhibiting adaptive immune resistance
The dynamics of T-cell responses are investigated in tumour tissue from patients with advanced melanoma who were treated with a PD-1-blocking monoclonal antibody, revealing that clinical efficacy of the treatment correlates with increased frequencies of pre-existing CD8
+
T cells and PD-1 and PD-L1 expression.
PD-1 blockade inhibits adaptive immune resistance
Therapies that target the human cell-surface programmed death-1 (PD-1) receptor have shown unprecedented clinical responses in a variety of cancer types. Here Paul Tumeh
et al
. investigate the dynamics of T-cell responses in tumour tissues of patients with advanced melanoma treated with pembrolizumab, a humanized monoclonal antibody directed against human PD-1. Clinical efficacy is shown to correlate with increased frequencies of pre-existing CD8
+
T cells and PD-1 and PD-L1 expression at the invasive tumour margin and within tumours.
Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types
1
,
2
,
3
,
4
,
5
. One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8
+
T cells (termed adaptive immune resistance)
6
,
7
. Here we show that pre-existing CD8
+
T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analysed samples from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumours, patients responding to treatment showed proliferation of intratumoral CD8
+
T cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8-, PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8
+
T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.
Journal Article
Challenges in permeability characterisation for modelling the manufacture of wind turbine blades
As wind turbine blades continue to increase in size, and market competition grows, lean manufacturing has become even more important for OEMs. The rapid development of new blade designs, with greater performance, and reduced production waste are driving the need for predictive modelling of the blade infusion process. Such simulations are reliant upon Darcy’s Law for the description of fluid flow through porous materials and therefore depend greatly on the permeability properties of the blade preform materials. The characterisation of fabric permeability, although unstandardised, has been well studied in recent years as the focus of numerous international benchmarking efforts. However, the effective permeability properties of infusion consumables, core materials, and pre-cast elements are not so well defined or validated, despite their significance on infusion behaviour. Hence, the great variety of preform materials, stacking configurations, geometric features, and transition regions in wind turbine blades present considerable challenges in terms of permeability characterisation and subsequent modelling. This article reviews some of the challenges, opportunities, and alternatives for characterising permeability in common blade preform materials, along with examples of how these properties have been applied in numerical models to better simulate the resin infusion manufacturing process for wind turbine blades.
Journal Article
IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4−CD8− entheseal resident T cells
Spondyloarthropathies are characterized by a distinct pattern of inflammation at distinct anatomical sites and are associated with elevated expression of interleukin 23 (IL-23). Daniel Cua and his colleagues identify an IL-23–responsive CD4
−
CD8
−
T cell population located within entheses. Systemic overexpression of IL-23 activates these cells and recapitulates aspects of the human disease in mice, and neutralization of IL-17 and IL-22 decreases pathology, suggesting new therapeutic targets for these disorders.
The spondyloarthropathies are a group of rheumatic diseases that are associated with inflammation at anatomically distal sites, particularly the tendon-bone attachments (entheses) and the aortic root. Serum concentrations of interleukin-23 (IL-23) are elevated and polymorphisms in the IL-23 receptor are associated with ankyosing spondylitis, however, it remains unclear whether IL-23 acts locally at the enthesis or distally on circulating cell populations. We show here that IL-23 is essential in enthesitis and acts on previously unidentified IL-23 receptor (IL-23R)
+
, RAR-related orphan receptor γt (ROR-γt)
+
CD3
+
CD4
−
CD8
−
, stem cell antigen 1 (Sca1)
+
entheseal resident T cells. These cells allow entheses to respond to IL-23
in vitro
—in the absence of further cellular recruitment—and to elaborate inflammatory mediators including IL-6, IL-17, IL-22 and chemokine (C-X-C motif) ligand 1 (CXCL1). Notably, the
in vivo
expression of IL-23 is sufficient to phenocopy the human disease, with the specific and characteristic development of enthesitis and entheseal new bone formation in the initial complete absence of synovitis. As in the human condition, inflammation also develops
in vivo
at the aortic root and valve, which are structurally similar to entheses. The presence of these entheseal resident cells and their production of IL-22, which activates signal transducer and activator of transcription 3 (STAT3)-dependent osteoblast-mediated bone remodeling, explains why dysregulation of IL-23 results in inflammation at this precise anatomical site.
Journal Article
On the creation of structured abrasive tools via multiple-pass rotary wire EDM: A geometrical model
Structured abrasive tools (SATs) are considered as one of the next-generation abrasive tool solutions due to their superior ability to transport cutting fluids into grinding zones to lower grinding temperature and therefore enable high-quality machined surfaces. There are several SAT fabrication methods including mechanical, electroplating, brazing, and laser-based methods. Mechanical methods cannot produce SATs with small-sized structures due to significant contact forces, while electroplating has poor controllability of abrasive grain allocations. Brazing requires special machines with high-precision motion control, while laser-based methods need significant efforts on laser parameter selection and optimization. With this, here, we present a multiple-pass rotary wire electrical discharge machining (MPRWEDM) method to address the aforementioned limitations. We also develop a theoretical model of the created kerf profile during the MPRWEDM so as to enable controllable fabrication of SATs. The model was experimentally validated, showing a decent relative error of 9.8%. The nonlinear multiple-pass effect was studied both analytically and experimentally. Based on MPRWEDM, not only the SAT with designed grooves but also the structured surface (having an array of pyramid geometries) generated by the SAT were successfully created, proving the great potential of MPRWEDM in controllable production of even more advanced tools.
Journal Article
Can I Talk about Shakespeare?
Can I (and you) talk sensibly about William Shakespeare's works? Some historicists see insuperable barriers in trying to understand utterances from different times and cultures, and some skeptics see such barriers in trying to read other minds. In Ludwig Wittgenstein's famous utterance about not understanding a talking lion, is the early modern Englishman Shakespeare one of those lions? Or can a magic key see past such barriers in one of the critical systems that we are offered? I argue that the answer to both questions is no.
Journal Article
Characterization of abscopal effects of intratumoral electroporation-mediated IL-12 gene therapy
Intratumoral electroporation-mediated IL-12 gene therapy (IT-pIL12/EP) has been shown to be safe and effective in clinical trials, demonstrating systemic antitumor effects with local delivery of this potent cytokine. We recently optimized our IL-12 gene delivery platform to increase transgene expression and efficacy in preclinical models. Here we analyze the immunological changes induced with the new IT-pIL12/EP platform in both electroporated and distant, non-electroporated lesions. IT-pIL12/EP-treated tumors demonstrated rapid induction of IL-12-regulated pathways, as well as other cytokines and chemokines pathways, and upregulation of antigen presentation machinery. The distant tumors showed an increase in infiltrating lymphocytes and gene expression changes indicative of a de novo immune response in these untreated lesions. Flow cytometric analyses revealed a KLRG1hi CD8+ effector T-cell population uniquely present in mice treated with IT-pIL12/EP. Despite being highly activated, this population expressed diminished levels of PD-1 when re-exposed to antigen in the PD-L1-rich tumor. Other T-cell exhaustion markers appeared to be downregulated in concert, suggesting an orchestrated “armoring” of these effector T cells against T-cell checkpoints when primed in the presence of IL-12 in situ. These cells may represent an important mechanism by which local IL-12 gene therapy can induce a systemic antitumor immune response without the associated toxicity of systemic IL-12 exposure.
Journal Article