A scoping review of factors influencing the implementation of liquid biopsy for cancer care.
Abstract Background: Liquid biopsy (LB) offers a promising, minimally invasive alternative to traditional tissue biopsies in cancer care, enabling real-time monitoring and personalized treatment. Despite its potential, the routine implementation of LB in clinical practice faces significant challenges. This scoping review examines the barriers and facilitators influencing the implementation of liquid biopsies into standard cancer care. Methods: Four academic databases (PubMed, Scopus, Embase, and Web of Science) were systematically searched without language restrictions. We included peer-reviewed articles that were published between January 2019 and March 2024 that focused on the implementation of LB in cancer care or described barriers and facilitators [...]
Multiomic profiling of checkpoint inhibitor-treated melanoma: Identifying predictors of response and resistance, and markers of biological discordance.
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Neoadjuvant Triplet Immune Checkpoint Blockade in Newly Diagnosed Glioblastoma.
Abstract Glioblastoma (GBM) is an aggressive primary adult brain tumor that rapidly recurs after standard-of-care treatments, including surgery, chemotherapy and radiotherapy. While immune checkpoint inhibitor therapies have transformed outcomes in many tumor types, particularly when used neoadjuvantly or as a first-line treatment, including in melanoma brain metastases, they have shown limited efficacy in patients with resected or recurrent GBM. The lack of efficacy has been attributed to the scarcity of tumor-infiltrating lymphocytes (TILs), an immunosuppressive tumor microenvironment and low tumor mutation burden typical of GBM tumors, plus exclusion of large molecules from the brain parenchyma. We hypothesized that upfront [...]
PKC-independent PI3K signalling diminishes PKC inhibitor sensitivity in uveal melanoma.
Abstract Protein kinase C (PKC) is activated downstream of gain-of-function GNAQ or GNA11 (GNAQ/GNA11) mutations in over 90% of uveal melanoma (UM). Phase I clinical trials of PKC inhibitors have shown modest response rates with no survival benefit in metastatic UM. Although PKC inhibitors actively suppress mitogen-activated protein kinase (MAPK) signalling in UM, the effect on other UM signalling cascades is not well understood. We examined the transcriptome of UM biopsies collected pre- and post-PKC inhibitor therapy and confirmed that MAPK, but not PI3K/AKT signalling, was inhibited early during treatment with the second-generation PKC inhibitor IDE196. Similarly, in GNAQ/GNA11-mutant [...]
The molecular and functional landscape of resistance to immune checkpoint blockade in melanoma.
Abstract Resistance to immune checkpoint inhibitor therapies in melanoma is common and remains an intractable clinical challenge. In this study, we comprehensively profile immune checkpoint inhibitor resistance mechanisms in short-term tumor cell lines and matched tumor samples from melanoma patients progressing on immune checkpoint inhibitors. Combining genome, transcriptome, and high dimensional flow cytometric profiling with functional analysis, we identify three distinct programs of immunotherapy resistance. Here we show that resistance programs include (1) the loss of wild-type antigen expression, resulting from tumor-intrinsic IFNγ signaling and melanoma de-differentiation, (2) the disruption of antigen presentation via multiple independent mechanisms affecting MHC [...]
Intratumoral CD16+ macrophages are associated with clinical outcomes of patients with metastatic melanoma treated with combination anti-PD-1 and anti-CTLA-4 therapy.
Abstract Purpose: This study characterizes intratumoural macrophage populations within baseline melanoma biopsies from patients with advanced melanoma who received either anti-PD-1 monotherapy or combination with anti-CTLA-4. Particularly, FcγRIIIa (CD16) expressing macrophage densities were investigated for associations with response and progression-free survival. Experimental design: Patients with advanced melanoma who received either anti-PD-1 monotherapy or combination anti-PD-1 and anti-CTLA-4 were retrospectively identified. Macrophage populations were analyzed within baseline melanoma biopsies via multiplex immunohistochemistry in relation to treatment outcomes. Results: Patients who responded to combination ICI contained higher CD16+ macrophage densities than those who did not respond (196 vs 7 cells/mm2; p [...]
IFNγ signaling sensitizes melanoma cells to BH3 Mimetics.
Abstract Immunotherapy targeting PD-1 and/or CTLA4 leads to durable responses in a proportion of patients with melanoma. However, many patients will not respond to these immune checkpoint inhibitors, and up to 60% of responding patients will develop treatment resistance. We describe a vulnerability in melanoma driven by immune cell activity that provides a pathway towards additional treatment options. This study evaluated short-term melanoma cell lines (referred to as PD1 PROG cells) derived from melanoma metastases that progressed on PD-1 inhibitor–based therapy. We show that the cytokine IFN-γ primes melanoma cells for apoptosis by promoting changes in the accumulation and [...]
Protein-based classification of melanoma differentiation subtypes.
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MHC Class I Deficiency in Solid Tumors and Therapeutic Strategies to Overcome It
Abstract It is now well accepted that the immune system can control cancer growth. However, tumors escape immune-mediated control through multiple mechanisms and the downregulation or loss of major histocompatibility class (MHC)-I molecules is a common immune escape mechanism in many cancers. MHC-I molecules present antigenic peptides to cytotoxic T cells, and MHC-I loss can render tumor cells invisible to the immune system. In this review, we examine the dysregulation of MHC-I expression in cancer, explore the nature of MHC-I-bound antigenic peptides recognized by immune cells, and discuss therapeutic strategies that can be used to overcome MHC-I deficiency in [...]
Repurposing Melanoma Chemotherapy to Activate Inflammasomes in the Treatment of BRAF/MAPK Inhibitor Resistant Melanoma.
Abstract The development of resistance to treatments of melanoma is commonly associated with an upregulation of the MAPK pathway and the development of an undifferentiated state. Previous studies have suggested that melanoma with these resistance characteristics may be susceptible to innate death mechanisms such as pyroptosis triggered by the activation of inflammasomes. In this study, we have taken cell lines from patients before and after the development of resistance to BRAF V600 inhibitors and exposed the resistant melanoma to temozolomide (a commonly used chemotherapy) with and without chloroquine to inhibit autophagy. It was found that melanoma with an inflammatory [...]