Publications by authors named "Katie E Lacy"

Article Synopsis
  • The study investigates how different types of senescent cells in the skin contribute to the development of cancer in patients with Familial Melanoma Syndrome (FMS), who have defects in the CDKN2A gene.
  • Melanocytes from FMS patients show lower p16 levels and higher DNA damage markers compared to fibroblasts, while patient fibroblasts also exhibit unusual behaviors, such as increased replicative capacity and defective senescence.
  • The findings suggest that the combination of DNA damage in melanocytes and impaired senescence in fibroblasts may weaken the immune response and enhance the risk of melanoma in these patients.
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  • Despite advancements in immunotherapies for melanoma, many patients still don't benefit due to current treatments mainly targeting T-cells rather than the more prevalent macrophages in the tumor environment.
  • Macrophages have a dual role: they can activate the immune response and kill cancer cells, but they can also aid in tumor growth and spread depending on their interaction with the tumor microenvironment.
  • A thorough understanding of macrophages' roles and interactions in melanoma, along with novel therapies aimed at them, is crucial for enhancing treatment outcomes for melanoma patients.
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Article Synopsis
  • - B cells play a crucial role in the immune response against tumors, particularly in melanoma, but their specific functions and characteristics have not been fully explored until now.
  • - In this study, researchers found that memory B cells are more prevalent in tumors than in the bloodstream and exhibit unique antibody profiles that indicate processes like clonal expansion and affinity maturation.
  • - The presence of tumor-associated B cells with autoimmune-like traits and high levels of antibodies related to both autoimmune diseases and cancer suggests a dysregulated immune response in melanoma patients.
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  • Despite existing checkpoint inhibitor therapies, about half of melanoma patients still struggle with poor outcomes.
  • A new engineered monoclonal IgE antibody targeting the CSPG4 antigen shows promise by binding to melanoma cells and enhancing immune responses.
  • In studies, this IgE therapy significantly improved survival and anti-tumor activity in models, suggesting its potential as an effective treatment option for melanoma patients.
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The application of monoclonal antibodies (mAbs) for the treatment of melanoma has significantly improved the clinical management of this malignancy over the last decade. Currently approved mAbs for melanoma enhance T cell effector immune responses by blocking immune checkpoint molecules PD-L1/PD-1 and CTLA-4. However, more than half of patients do not benefit from treatment.

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Article Synopsis
  • * In melanoma patients, TGF-β-expressing B cells form clusters in the tumor microenvironment and interact with T cells and regulatory T cells (Tregs) through specific signals, suggesting a complex relationship that can contribute to immune suppression.
  • * The study highlights how B cells from melanoma patients may promote Treg differentiation and support T-helper cell functions, particularly when combined with anti-PD-1 treatment, indicating potential therapeutic implications for boosting anti-tumor immunity.
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Triple-negative breast cancers (TNBC) expressing PD-L1 qualify for checkpoint inhibitor immunotherapy. Cyclin E/CDK2 is a potential target axis in TNBC; however, small-molecule drugs at efficacious doses may be associated with toxicity, and treatment alongside immunotherapy requires investigation. We evaluated CDK inhibition at suboptimal levels and its anti-tumor and immunomodulatory effects.

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Article Synopsis
  • - Recent advancements in melanoma treatment involve small-molecule inhibitors that target the MAPK pathway and immune checkpoint blockade, yet the 5-year survival rate for advanced cases is still about 50%.
  • - The review focuses on how MAPK inhibitors, particularly BRAFi, affect the tumor microenvironment by changing inflammatory cytokine levels and immune cell activity, and considers potential treatment combinations.
  • - Expert insights suggest that using MAPK inhibitors with existing therapies, like checkpoint inhibitors and adoptive cell therapies, could enhance immune responses and improve long-term patient outcomes in melanoma treatment.
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Article Synopsis
  • * They can also be involved in chronic inflammation, infections, and potentially have roles in cancer, although they haven't been thoroughly studied in this context.
  • * Researchers are analyzing basophil gene expression in cancer patients to see how they relate to clinical outcomes and exploring their potential to predict reactions to cancer treatments and monitor patient responses.
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Human B cells and their expressed antibodies are crucial in conferring immune protection. Identifying pathogen-specific antibodies following infection is possible due to enhanced humoral immunity against well-described molecules on the pathogen surface. However, screening for cancer-reactive antibodies remains challenging since target antigens are often not identified a priori and the frequency of circulating B cells recognizing cancer cells is likely very low.

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The unmet clinical need for effective treatments in ovarian cancer has yet to be addressed using monoclonal antibodies (mAbs), which have largely failed to overcome tumour-associated immunosuppression, restrict cancer growth, and significantly improve survival. In recent years, experimental mAb design has moved away from solely targeting ovarian tumours and instead sought to modulate the wider tumour microenvironment (TME). Tumour-associated macrophages (TAMs) may represent an attractive therapeutic target for mAbs in ovarian cancer due to their high abundance and close proximity to tumour cells and their active involvement in facilitating several pro-tumoural processes.

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The incidence of cutaneous malignant melanoma is rising globally and is projected to continue to rise. Advances in immunotherapy over the last decade have demonstrated that manipulation of the immune cell compartment of tumours is a valuable weapon in the arsenal against cancer; however, limitations to treatment still exist. Cutaneous melanoma lesions feature a dense cell infiltrate, coordinated by chemokines, which control the positioning of all immune cells.

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In breast cancer, humoral immune responses may contribute to clinical outcomes, especially in more immunogenic subtypes. Here, we investigated B lymphocyte subsets, immunoglobulin expression, and clonal features in breast tumors, focusing on aggressive triple-negative breast cancers (TNBC). In samples from patients with TNBC and healthy volunteers, circulating and tumor-infiltrating B lymphocytes (TIL-B) were evaluated.

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Background: Cancer immunotherapy with monoclonal antibodies and chimeric antigen receptor (CAR) T cell therapies can benefit from selection of new targets with high levels of tumor specificity and from early assessments of efficacy and safety to derisk potential therapies.

Methods: Employing mass spectrometry, bioinformatics, immuno-mass spectrometry and CRISPR/Cas9 we identified the target of the tumor-specific SF-25 antibody. We engineered IgE and CAR T cell immunotherapies derived from the SF-25 clone and evaluated potential for cancer therapy.

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The contributions of the humoral immune response to melanoma are now widely recognized, with reports of positive prognostic value ascribed to tumor-infiltrating B cells (TIL-B) and increasing evidence of B cells as key predictors of patient response to treatment. There are disparate views as to the pro- and anti-tumor roles of B cells. B cells appear to play an integral role in forming tumor-associated tertiary lymphoid structures (TLSs) which can further modulate T cell activation.

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Cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and the Programmed Death Receptor 1 (PD-1) are immune checkpoint molecules that are well-established targets of antibody immunotherapies for the management of malignant melanoma. The monoclonal antibodies, Ipilimumab, Pembrolizumab, and Nivolumab, designed to interfere with T cell inhibitory signals to activate immune responses against tumors, were originally approved as monotherapy. Treatment with a combination of immune checkpoint inhibitors may improve outcomes compared to monotherapy in certain patient groups and these clinical benefits may be derived from unique immune mechanisms of action.

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Article Synopsis
  • IgE plays a crucial role in enhancing the immune response during infections and has been shown to aid monocyte and macrophage recruitment, which is important for fighting tumors.
  • The study found that IgE stimulation of human monocytes leads to the activation of pro-inflammatory signals and improved tumor-killing functions, which could be beneficial for cancer treatment.
  • Insights from this research can help develop new IgE monoclonal antibody therapies aimed at boosting immune responses against cancer.
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Antibody-Drug Conjugates (ADCs) developed as a targeted treatment approach to deliver toxins directly to cancer cells are one of the fastest growing classes of oncology therapeutics, with eight ADCs and two immunotoxins approved for clinical use. However, selection of an optimum target and payload combination, to achieve maximal therapeutic efficacy without excessive toxicity, presents a significant challenge. We have developed a platform to facilitate rapid and cost-effective screening of antibody and toxin combinations for activity and safety, based on streptavidin-biotin conjugation.

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Despite emerging targeted and immunotherapy treatments, no monoclonal antibodies or antibody-drug conjugates (ADCs) directly targeting tumor cells are currently approved for melanoma therapy. The tumor-associated antigen chondroitin sulphate proteoglycan 4 (CSPG4), a neural crest glycoprotein over-expressed on 70% of melanomas, contributes to proliferative signaling pathways, but despite highly tumor-selective expression it has not yet been targeted using ADCs. We developed a novel ADC comprising an anti-CSPG4 antibody linked to a DNA minor groove-binding agent belonging to the novel pyrridinobenzodiazepine (PDD) class.

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Immune and inflammatory cascades may play multiple roles in ovarian cancer. We aimed to identify relationships between expression of immune and inflammatory mediators and patient outcomes. We interrogated differential gene expression of 44 markers and marker combinations (n = 1,978) in 1,656 ovarian carcinoma patient tumors, alongside matched 5-year overall survival (OS) data in silico.

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Background: Antibody Fc-driven engagement of macrophages is critical for evoking cellular activation and effector functions and influencing tumour-associated macrophage (TAM) recruitment. We previously reported that IgE class antibodies promote restriction of cancer growth in rodent models associated with significant TAM infiltration. However, the human macrophage-associated IgE-Fc Receptor (FcεR) axis remains unexplored.

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Article Synopsis
  • The immune system uses checkpoint pathways to manage responses, prevent autoimmunity, and regulate overall immune function, but cancer cells can exploit these pathways to evade immune detection and thrive.
  • Blocking antibodies targeting molecules like CTLA-4 and PD-1/PD-L1 can enhance immune responses against tumors, leading to significant success in melanoma treatment, although not every patient benefits and some may develop resistance.
  • Research is ongoing to explore combination therapies using existing and new checkpoint inhibitors (like A2AR, LAG-3, and IDO) to improve patient outcomes and survival rates compared to single-agent treatments.
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Article Synopsis
  • - The study presents a method for identifying single B cells that produce specific antibodies by using antigen-conjugated fluorescent beads, specifically focusing on the Folate Receptor alpha (FRα) as a model antigen.
  • - Researchers used a mouse B cell line with a chimeric antibody targeting FRα to sort and analyze single antibody-expressing cells, allowing them to isolate and clone the antibody's genetic components.
  • - The method proved effective in identifying antigen-specific B cells from mixed human immune cell populations, successfully generating monoclonal antibodies that recognize specific cancer-related antigens, paving the way for deeper insights into individual immune responses.
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Overexpression of the chondroitin sulfate proteoglycan 4 (CSPG4) has been associated with the pathology of multiple types of such as melanoma, breast cancer, squamous cell carcinoma, mesothelioma, neuroblastoma, adult and pediatric sarcomas, and some hematological cancers. CSPG4 has been reported to exhibit a role in the growth and survival as well as in the spreading and metastasis of tumor cells. CSPG4 is overexpressed in several malignant diseases, while it is thought to have restricted and low expression in normal tissues.

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