Publications by authors named "Shannon J Turley"

Single-cell RNA-seq (scRNA-seq) has profiled hundreds of millions of human cells across organs, diseases, development, and perturbations to date. Mining these growing atlases could reveal cell-disease associations, discover cell states in unexpected tissue contexts, and relate in vivo biology to in vitro models. These require a common measure of cell similarity across the body and an efficient way to search.

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One driver of the high failure rates of clinical trials for therapeutic cancer vaccines is likely the inability to sufficiently engage conventional dendritic cells (cDCs), the antigen-presenting cell (APC) subset that is specialized in priming antitumor T cells. Here, we demonstrate that, relative to vaccination with an injectable mesoporous silica rod (MPS) vaccine alone (Vax), combining MPS vaccines with CD122-biased IL-2/anti-IL-2 antibody complexes (IL-2cx) drives ~3-fold expansion of cDCs at the vaccination sites, vaccine-draining lymph nodes, and spleens of treated mice. Furthermore, relative to Vax alone, Vax+IL-2cx led to a ~3-fold increase in the numbers of CD8 T cells and ~15-fold increase in the numbers of NK cells at the vaccination site.

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Macrophages exhibit remarkable functional plasticity, a requirement for their central role in tissue homeostasis. During chronic inflammation, macrophages acquire sustained inflammatory 'states' that contribute to disease, but there is limited understanding of the regulatory mechanisms that drive their generation. Here we describe a systematic functional genomics approach that combines genome-wide phenotypic screening in primary murine macrophages with transcriptional and cytokine profiling of genetic perturbations in primary human macrophages to uncover regulatory circuits of inflammatory states.

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Following immunization, lymph nodes dynamically expand and contract. The mechanical and cellular changes enabling the early-stage expansion of lymph nodes have been characterized, yet the durability of such responses and their implications for adaptive immunity and vaccine efficacy are unknown. Here, by leveraging high-frequency ultrasound imaging of the lymph nodes of mice, we report more potent and persistent lymph-node expansion for animals immunized with a mesoporous silica vaccine incorporating a model antigen than for animals given bolus immunization or standard vaccine formulations such as alum, and that durable and robust lymph-node expansion was associated with vaccine efficacy and adaptive immunity for 100 days post-vaccination in a mouse model of melanoma.

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In this issue of Cell Reports Medicine, Qin et al. present a comprehensive single-cell transcriptomics analysis of the tumor microenvironment of rectal cancer tumors before and after neoadjuvant chemotherapy.

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The cancer-immunity cycle provides a framework to understand the series of events that generate anti-cancer immune responses. It emphasizes the iterative nature of the response where the killing of tumor cells by T cells initiates subsequent rounds of antigen presentation and T cell stimulation, maintaining active immunity and adapting it to tumor evolution. Any step of the cycle can become rate-limiting, rendering the immune system unable to control tumor growth.

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Article Synopsis
  • TGFβ signaling contributes to a lack of response to immune checkpoint therapies in advanced cancers, especially in tumors that exclude immune cells.
  • The study highlights that TGFβ and PD-L1 hinder the growth and replenishment of effective CD8 T cells within tumors, keeping them dysfunctional.
  • Combining therapies that block TGFβ and PD-L1 enhances the movement and effectiveness of CD8 T effector cells, while also transforming the tumor environment to be more supportive of the immune response, indicating the necessity of IFNγ signaling in this process.
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  • The immune phenotype of tumors plays a crucial role in predicting how well they will respond to immunotherapy, with immune-inflamed tumors typically having better responses due to high T cell infiltration.
  • Not all inflamed tumors are effective against therapy, and tumors lacking T cells (immune desert) or pushing T cells to the edges (immune excluded) show even lower response rates.
  • The new technique called skin tumor array by microporation (STAMP) allows researchers to study the development and dynamics of tumor immune phenotypes in real-time, revealing that local factors and T cell recruitment are key to understanding tumor rejection and therapy success.
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The lymph node (LN) is home to resident macrophage populations that are essential for immune function and homeostasis, but key factors controlling this niche are undefined. Here, we show that fibroblastic reticular cells (FRCs) are an essential component of the LN macrophage niche. Genetic ablation of FRCs caused rapid loss of macrophages and monocytes from LNs across two in vivo models.

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Article Synopsis
  • Immune checkpoint inhibitors (ICIs) like atezolizumab are effective cancer treatments, but many patients still face therapeutic resistance.
  • High levels of interleukin 6 (IL-6) correlate with a poor response to atezolizumab in advanced cancers, indicating a potential target for overcoming resistance.
  • Combining PD-L1 blockade with IL-6 receptor inhibition shows promising results in preclinical studies by enhancing the effectiveness of anti-tumor immune responses, suggesting IL-6 signaling inhibitors could improve ICI therapies in cancer patients.
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Recent single-cell studies of cancer in both mice and humans have identified the emergence of a myofibroblast population specifically marked by the highly restricted leucine-rich-repeat-containing protein 15 (LRRC15). However, the molecular signals that underlie the development of LRRC15 cancer-associated fibroblasts (CAFs) and their direct impact on anti-tumour immunity are uncharacterized. Here in mouse models of pancreatic cancer, we provide in vivo genetic evidence that TGFβ receptor type 2 signalling in healthy dermatopontin universal fibroblasts is essential for the development of cancer-associated LRRC15 myofibroblasts.

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Unlabelled: It is currently accepted that cancer-associated fibroblasts (CAF) participate in T-cell exclusion from tumor nests. To unbiasedly test this, we used single-cell RNA sequencing coupled with multiplex imaging on a large cohort of lung tumors. We identified four main CAF populations, two of which are associated with T-cell exclusion: (i) MYH11+αSMA+ CAF, which are present in early-stage tumors and form a single cell layer lining cancer aggregates, and (ii) FAP+αSMA+ CAF, which appear in more advanced tumors and organize in patches within the stroma or in multiple layers around tumor nests.

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Recent studies have defined a novel population of PD-1+ TCF-1+ stem-like CD8 T cells in chronic infections and cancer. These quiescent cells reside in lymphoid tissues, are critical for maintaining the CD8 T cell response under conditions of persistent antigen, and provide the proliferative burst after PD-1 blockade. Here we examined the role of TGF-β in regulating the differentiation of virus-specific CD8 T cells during chronic LCMV infection of mice.

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Recent studies have identified a unique cancer-associated fibroblast (CAF) population termed antigen-presenting CAFs (apCAFs), characterized by the expression of major histocompatibility complex class II molecules, suggesting a function in regulating tumor immunity. Here, by integrating multiple single-cell RNA-sequencing studies and performing robust lineage-tracing assays, we find that apCAFs are derived from mesothelial cells. During pancreatic cancer progression, mesothelial cells form apCAFs by downregulating mesothelial features and gaining fibroblastic features, a process induced by interleukin-1 and transforming growth factor β.

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The cancer-associated fibroblast (CAF) marker podoplanin (PDPN) is generally correlated with poor clinical outcomes in cancer patients and thus represents a promising therapeutic target. Despite its biomedical relevance, basic aspects of PDPN biology such as its cellular functions and cell surface ligands remain poorly uncharacterized, thus challenging drug development. Here, we utilize a high throughput platform to elucidate the PDPN cell surface interactome, and uncover the neutrophil protein CD177 as a new binding partner.

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Article Synopsis
  • Myeloid cells interact continuously with stromal cells and their surrounding matrix, and the study focused on the role of the collagen receptor LAIR1 in these processes.
  • LAIR1 was found to be highly expressed in myeloid cells, particularly in non-classical monocytes, and was shown to bind to the stromal factor Colec12, influencing fundamental cellular pathways.
  • Mice lacking LAIR1 displayed reduced monocyte populations and enhanced melanoma growth, indicating that LAIR1 is important for the health and functionality of myeloid cells, relevant for both normal physiological processes and disease outcomes.
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Fibroblasts, custodians of tissue architecture and function, are no longer considered a monolithic entity across tissues and disease indications. Recent advances in single-cell technologies provide an unrestricted, high-resolution view of fibroblast heterogeneity that exists within and across tissues. In this review, we summarize a compendium of single-cell transcriptomic studies and provide a comprehensive accounting of fibroblast subsets, many of which have been described to occupy specific niches in tissues at homeostatic and pathologic states.

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Fibroblasts are non-haematopoietic structural cells that define the architecture of organs, support the homeostasis of tissue-resident cells and have key roles in fibrosis, cancer, autoimmunity and wound healing. Recent studies have described fibroblast heterogeneity within individual tissues. However, the field lacks a characterization of fibroblasts at single-cell resolution across tissues in healthy and diseased organs.

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Fibroblasts and macrophages are present in all tissues, and mounting evidence supports that these cells engage in direct communication to influence the overall tissue microenvironment and affect disease outcomes. Here, we review the current understanding of the molecular mechanisms that underlie fibroblast-macrophage interactions in health, fibrosis, and cancer. We present an integrated view of fibroblast-macrophage interactions that is centered on the CSF1-CSF1R axis and discuss how additional molecular programs linking these cell types can underpin disease onset, progression, and resolution.

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Repair of the intestinal epithelium is tightly regulated to maintain homeostasis. The response after epithelial damage needs to be local and proportional to the insult. How different types of damage are coupled to repair remains incompletely understood.

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Distinct T cell infiltration patterns, i.e., immune infiltrated, excluded, and desert, result in different responses to cancer immunotherapies.

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Fibroblastic reticular cells (FRCs) are specialized stromal cells that define tissue architecture and regulate lymphocyte compartmentalization, homeostasis, and innate and adaptive immunity in secondary lymphoid organs (SLOs). In the present study, we used single-cell RNA sequencing (scRNA-seq) of human and mouse lymph nodes (LNs) to identify a subset of T cell-zone FRCs defined by the expression of Gremlin1 (Grem1) in both species. Grem1-CreER knock-in mice enabled localization, multi-omics characterization and genetic depletion of Grem1 FRCs.

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TGFβ signalling has key roles in cancer progression: most carcinoma cells have inactivated their epithelial antiproliferative response and benefit from increased TGFβ expression and autocrine TGFβ signalling through effects on gene expression, release of immunosuppressive cytokines and epithelial plasticity. As a result, TGFβ enables cancer cell invasion and dissemination, stem cell properties and therapeutic resistance. TGFβ released by cancer cells, stromal fibroblasts and other cells in the tumour microenvironment further promotes cancer progression by shaping the architecture of the tumour and by suppressing the antitumour activities of immune cells, thus generating an immunosuppressive environment that prevents or attenuates the efficacy of anticancer immunotherapies.

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Upon viral infection, stressed or damaged cells can release alarmins like IL-33 that act as endogenous danger signals alerting innate and adaptive immune cells. IL-33 coming from nonhematopoietic cells has been identified as important factor triggering the expansion of antiviral CD8 T cells. In LN the critical cellular source of IL-33 is unknown, as is its potential cell-intrinsic function as a chromatin-associated factor.

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