Tertiary lymphoid structures (TLS) are ectopic lymphoid formations that form within nonlymphoid tissue. They share structural and functional characteristics with secondary lymphoid structures such as ...lymph nodes and can contain B-cell follicles and germinal centers surrounded by a T-cell region. TLS have been described in several types of cancers and are usually associated with positive patient outcomes. However, TLS differ vastly in cellular composition and location within tissue types. In this review, we discuss factors confounding the interpretation of the evidence for a prognostic role for TLS in cancer and frame these factors in the context of translation to regular clinical use.
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Bacteria biohybrid-based vaccine delivery systems, which integrate a vaccine carrier with live non-pathogenic bacteria, are hypothesized to have improved immunostimulating potential. ...The aim of this study was to develop oral bacteria biohybrid-based vaccines to treat a mouse model of colorectal cancer. E. coli were combined with tumor antigen- and adjuvant-containing emulsions or liposomes. Emulsion and liposome biohybrid vaccines demonstrated in vitro and in vivo therapeutic potential. Bacteria biohybrid vaccines significantly increased the expression of CD40+, CD80+ and CD86+ on murine bone marrow-derived dendritic cells. Mice vaccinated with emulsion biohybrid vaccines had an increased CD8+ T cell infiltration into tumors and developed three-fold smaller tumors compared to the mice that received emulsion vaccine without E. coli.
Lipid-based formulations (liposomes and W/O/W double emulsions) were developed for oral delivery of a peptide vaccine to treat colorectal cancer. Immune responses generated following oral delivery of ...the vaccines were examined in tumour-free mice and in mice with an established orthotopic colorectal cancer. Vaccination of mice resulted in activation of lymphocyte subsets in the lymph nodes, spleen and tumour and reduced tumour growth.
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The aim of this study was to develop an oral vaccine that could be used to treat colorectal cancer. Oral vaccines are technically challenging to develop due to the harsh gastric environment but have numerous benefits including high patient acceptability and the potential to stimulate local mucosal immune responses. Therapeutic vaccines are being investigated as options to treat cancer and the generation of local mucosal immunity may be of benefit in the treatment of gastrointestinal cancers. Novel oral vaccines consisting of a long tumour peptide and the TLR2 (Toll-like receptor 2) ligand Pam2Cys, formulated in either liposomes or W/O/W double emulsions, were developed. Oral dosing with the emulsion vaccine increased the numbers of activated T cells, B cells and CD11c+F4/80+CD11b+ cells compared to mice that received control vaccines. In an orthotopic mouse model of colorectal cancer these immunological changes were associated with a seven-fold reduction in tumour size.
Research into the health benefits of probiotics has growing interest. Reported benefits of probiotic consumption range from the improvement of intestinal function to immune support. However, trials ...of probiotics lack the standardisation required to judge efficacy. It is important to acknowledge that probiotic products include a range of bacterial species and strains that can have varied effects. In this article, we address the importance of correctly interpreting trials of proposed probiotics. We discuss the necessity to treat probiotic bacterial strains independently, and to communicate findings consistently through both data reporting and product labelling. Finally, we propose a new approach to study the health effects of probiotics in the future.
Inflammatory Bowel Diseases (IBD) are difficult to model as freshly acquired tissues are short-lived, provide data as a snapshot in time, and are not always accessible. Many patients with IBD are ...non-responders to first-line treatments, and responders are prone to developing resistance to treatment over time-resulting in reduced patient quality of life, increased time to remission, and potential relapse. IBD is heterogenous and we are yet to fully understand the mechanisms of disease; thus, our ability to diagnose and prescribe optimal treatment remains ineffective. Intestinal organoids are derived from patient tissues expanded
. Organoids offer unique insight into individual patient disease and are a potential route to personalized treatments. However, organoid models do not contain functional microbial and immune cell components. In this review, we discuss immune cell subsets in the context of IBD, and the requirement of immune cell and microbial components in organoid models for IBD research.
The frequency of circulating or tumour‐infiltrating regulatory T cells (Tregs) has been associated with poor patient survival in many cancers including breast, melanoma and lung. It has been ...hypothesised that Tregs impact the anti‐tumour function of effector T cells, resulting in worse outcomes for patients. However, high infiltrates of Tregs have been associated with a positive outcome of patients in a minority of cancers including colorectal, bladder and oesophageal. In addition, many studies have shown no impact of Tregs in patient outcome. Traditionally, research has identified Tregs as forkhead box P3 (FOXP3+) T cells in order to make such associations. Recently, it has become evident that regulatory populations are very heterogeneous, and this heterogeneity is essential for Treg function. Treg heterogeneity likely affects predictions of patient outcome, and different Treg populations may have different influences on tumours. The study of Tregs in cancer must include a better definition of the cells analysed. This review will focus primarily on colorectal cancer in humans, due to mixed data on the impact of Tregs on patient outcome in this disease.
Oestrogen receptor-positive (ER+) breast cancer is commonly treated using endocrine therapies such as aromatase inhibitors which block synthesis of oestradiol, but the influence of this therapy on ...the immune composition of breast tumours has not been fully explored. Previous findings suggest that tumour infiltrating lymphocytes and immune-related gene expression may be altered by treatment with aromatase inhibitors. However, whether these changes are a direct result of impacts on the host immune system or mediated through tumour cells is not known. We aimed to investigate the effect of oestrogen deprivation on the expression of chemokines and immune infiltration in vitro and in an ER+ immunocompetent mouse model.
RT-qPCR and a bead-based Bioplex system were used to investigate the expression of chemokines in MCF-7 breast cancer cells deprived of oestrogen. A migration assay and flow cytometry were used to measure the migration of human peripheral blood mononuclear cells (PBMCs) to MCF-7 cells grown without the main biologically active oestrogen, oestradiol. Using flow cytometry and immunohistochemistry, we examined the immune cell infiltrate into tumours created by injecting SSM3 ER+ breast cancer cells into wild-type, immunocompetent 129/SvEv mice.
This study demonstrates that oestrogen deprivation increases breast cancer secretion of TNF, CCL5, IL-6, IL-8, and CCL22 and alters total human peripheral blood mononuclear cell migration in an in vitro assay. Oestrogen deprivation of breast cancer cells increases migration of CD4+ T cells and decreases migration of CD11c+ and CD14+ PBMC towards cancer cells. PBMC migration towards breast cancer cells can be reduced by treatment with the non-steroidal anti-inflammatory drugs, aspirin and celecoxib. Treatment with endocrine therapy using the aromatase inhibitor letrozole increases CD4+ T cell infiltration into ER+ breast cancer tumours in immune competent mice.
These results suggest that anti-oestrogen treatment of ER+ breast cancer cells can alter cytokine production and immune cells in the area surrounding the cancer cells. These findings may have implications for the combination and timing of anti-oestrogen therapies with other therapies.
The advent of mass cytometry has dramatically increased the parameter limit for immunological analysis. New approaches to analysing high parameter cytometry data have been developed to ease analysis ...of these complex datasets. Many of these methods assign cells into population clusters based on protein expression similarity.
Here we introduce an additional method, termed Brick plots, to visualize these cluster phenotypes in a simplified and intuitive manner. The Brick plot method generates a two-dimensional barcode that displays the phenotype of each cluster in relation to the entire dataset. We show that Brick plots can be used to visualize complex mass cytometry data, both from fundamental research and clinical trials, as well as flow cytometry data.
Brick plots represent a new approach to visualize complex immunological data in an intuitive manner.
CD8+ T cells are important in the control of viral infections and cancers because of their cytolytic activity. A vaccine able to generate these cells could be beneficial in the prevention or ...treatment of these diseases. Chitosan hydrogel is a promising vaccine formulation that has previously been shown to generate effector CD8+ T cells in a mouse model. This vaccine promotes sustained release of antigen and adjuvant, which generates a robust effector response. For longer lasting immunity, a memory population of these CD8+ T cells is required to control further disease. We found that vaccination with chitosan hydrogel or dendritic cells using ovalbumin protein as a model antigen and Quil‐A adjuvant provided protection in a subcutaneous melanoma challenge 30 days later. Ovalbumin‐specific memory CD8+ T cells were detectable following vaccination with the chitosan hydrogel but not the dendritic cell vaccine and an in vivo cytotoxicity assay demonstrated specific lysis of target cells in chitosan hydrogel vaccinated mice but not those receiving dendritic cell vaccination. These results demonstrate that vaccination with chitosan hydrogel is equally effective as dendritic cell vaccination in tumour protection but has more readily detectable immune correlates of protection. This may be advantageous in predetermining protection in vaccinated individuals.
Human intestinal organoids (hIOs) have potential as a model for investigating intestinal diseases. The hIO system faces logistic challenges including limited access to biopsies or low expression of ...epithelial cell types. Previous research identified the feasibility of tissue from the transverse (TC) or sigmoid colon (SC), or from cryopreserved biopsies from regions of the gastrointestinal tract. We aimed to create a protocol for robust hIO generation that could be implemented across multiple centres, allowing for development of a consistent biobank of hIOs from diverse patients.
TC and SC hIOs were expanded from fresh or frozen biopsies with standard or refined media. The expression of epithelial cells was evaluated via PCR. Growth of TC and SC hIO from healthy donors was reproducible from freshly acquired and frozen biopsies. A refined media including insulin-like growth factor (IGF)-1 and fibroblast growth factor (FGF)-2 enabled the expression of epithelial cells, including higher expression of goblet cells and enterocytes compared to standard organoid media. We identified a consistent time point where hIOs generated from frozen biopsies reflect similar hIO composition from freshly acquired samples. Feasibility of hIOs as a tool for research and clinical use, including the use of frozen biopsies, was demonstrated.
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